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Kausar MA, Anwar S, Khan YS, Saleh AA, Ahmed MAA, Kaur S, Iqbal N, Siddiqui WA, Najm MZ. Autophagy and Cancer: Insights into Molecular Mechanisms and Therapeutic Approaches for Chronic Myeloid Leukemia. Biomolecules 2025; 15:215. [PMID: 40001518 PMCID: PMC11853340 DOI: 10.3390/biom15020215] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2024] [Revised: 01/20/2025] [Accepted: 01/27/2025] [Indexed: 02/27/2025] Open
Abstract
Autophagy is a critical cellular process that maintains homeostasis by recycling damaged or aberrant components. This process is orchestrated by a network of proteins that form autophagosomes, which engulf and degrade intracellular material. In cancer, autophagy plays a dual role: it suppresses tumor initiation in the early stages but supports tumor growth and survival in advanced stages. Chronic myeloid leukemia (CML), a hematological malignancy, is characterized by the Philadelphia chromosome, a chromosomal abnormality resulting from a translocation between chromosomes 9 and 22. Autophagy has emerged as a key factor in CML pathogenesis, promoting cancer cell survival and contributing to resistance against tyrosine kinase inhibitors (TKIs), the primary treatment for CML. Targeting autophagic pathways is being actively explored as a therapeutic approach to overcome drug resistance and enhance cancer cell death. Recent research highlights the intricate interplay between autophagy and CML progression, underscoring its role in disease biology and treatment outcomes. This review aims to provide a comprehensive analysis of the molecular and cellular mechanisms underlying CML, with a focus on the therapeutic potential of targeting autophagy.
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MESH Headings
- Humans
- Autophagy/drug effects
- Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy
- Leukemia, Myelogenous, Chronic, BCR-ABL Positive/pathology
- Leukemia, Myelogenous, Chronic, BCR-ABL Positive/genetics
- Leukemia, Myelogenous, Chronic, BCR-ABL Positive/metabolism
- Protein Kinase Inhibitors/therapeutic use
- Protein Kinase Inhibitors/pharmacology
- Drug Resistance, Neoplasm/drug effects
- Animals
- Antineoplastic Agents/therapeutic use
- Antineoplastic Agents/pharmacology
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Affiliation(s)
- Mohd Adnan Kausar
- Department of Biochemistry, College of Medicine, University of Ha’il, Hail 55476, Saudi Arabia;
| | - Sadaf Anwar
- Department of Biochemistry, College of Medicine, University of Ha’il, Hail 55476, Saudi Arabia;
| | - Yusuf Saleem Khan
- Department of Anatomy, College of Medicine, University of Ha’il, Hail 55476, Saudi Arabia;
| | - Ayman A. Saleh
- Department of Pathology, College of Medicine, University of Ha’il, Hail 55476, Saudi Arabia;
| | | | - Simran Kaur
- School of Biosciences, Apeejay Stya University, Sohna, Gurugram 122103, Haryana, India;
| | - Naveed Iqbal
- Department of Obstetrics and Gynecology, College of Medicine, University of Ha’il, Ha’il 55476, Saudi Arabia;
| | - Waseem Ahmad Siddiqui
- Interdisciplinary Biotechnology Unit, Aligarh Muslim University, Aligarh 202001, Uttar Pradesh, India;
| | - Mohammad Zeeshan Najm
- School of Biosciences, Apeejay Stya University, Sohna, Gurugram 122103, Haryana, India;
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Xu N, Dao FT, Shi ZY, Sun K, Qin YZ. WT1 together with RUNX1::RUNX1T1 targets DUSP6 to dampen ERK activity in acute myeloid leukaemia. Br J Haematol 2024; 205:1848-1859. [PMID: 39191510 DOI: 10.1111/bjh.19721] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2024] [Accepted: 08/11/2024] [Indexed: 08/29/2024]
Abstract
Wilms' tumour 1 (WT1) can function as an oncogene or a tumour suppressor. Our previous clinical cohort studies showed that low WT1 expression at diagnosis independently predicted poor outcomes in acute myeloid leukaemia (AML) with RUNX1::RUNX1T1, whereas it had an opposite role in AML with non-favourable cytogenetic risk (RUNX1::RUNX1T1-deficient). The molecular mechanism by which RUNX1::RUNX1T1 affects the prognostic significance of WT1 in AML remains unknown. In the present study, first we validated the prognostic significance of WT1 expression in AML. Then by using the established transfected cell lines and xenograft tumour model, we found that WT1 suppresses proliferation and enhances effect of cytarabine in RUNX1::RUNX1T1(+) AML but has opposite functions in AML cells without RUNX1::RUNX1T1. Furthermore, as a transcription factor, WT1 physically interacts with RUNX1::RUNX1T1 and acts as a co-factor together with RUNX1::RUNX1T1 to activate the expression of its target gene DUSP6 to dampen extracellular signal-regulated kinase (ERK) activity. When RUNX1::RUNX1T1-deficient, WT1 can activate the mitogen-activated extracellular signal-regulated kinase/ERK axis but not through targeting DUSP6. These results provide a mechanism by which WT1 together with RUNX1::RUNX1T1 suppresses cell proliferation through WT1/DUSP6/ERK axis in AML. The current study provides an explanation for the controversial prognostic significance of WT1 expression in AML patients.
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Affiliation(s)
- Nan Xu
- Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing, China
| | - Feng-Ting Dao
- Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing, China
| | - Zong-Yan Shi
- Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing, China
| | - Kai Sun
- Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing, China
| | - Ya-Zhen Qin
- Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing, China
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Márton A, Veres KB, Erdődi F, Udvardy M, Illés Á, Rejtő L. The roles of phosphorylation of signaling proteins in the prognosis of acute myeloid leukemia. Pathol Oncol Res 2024; 30:1611747. [PMID: 39035053 PMCID: PMC11257863 DOI: 10.3389/pore.2024.1611747] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/26/2024] [Accepted: 06/12/2024] [Indexed: 07/23/2024]
Abstract
Signaling pathways of Retinoblastoma (Rb) protein, Akt-kinase, and Erk-kinase (extracellular signal-regulated kinase) have an important role in the pathogenesis of acute myeloid leukemia. Constitutive activation of these proteins by phosphorylation contributes to cell survival by regulation of cell cycle, proliferation and proapoptotic signaling processes. According to previous data phosphorylated forms of these proteins represent a worse outcome for cancer patients. We investigated the presence of phosphorylated Rb (P-Rb), Akt (P-Akt) and Erk (P-Erk) proteins by Western blot technique using phospho-specific antibodies in bone marrow or peripheral blood samples of 69 AML patients, 36 patients with myelodysplastic syndrome (MDS) and 10 healthy volunteers. Expression level of PTEN (Phosphatase and tensin homolog) and PHLPP (PH domain and leucine-rich repeat Protein Phosphatase) phosphatases, the negative regulators of Akt kinase pathway were also examined. We tested the effect of these proteins on survival and on the correlation with known prognostic features in AML. We found 46.3% of AML patients had detectable P-Rb, 34.7% had P-Akt and 28.9% had P-Erk protein. 66.1% of patients expressing PTEN, 38.9% PHLPP, 37.2% both PTEN and PHLPP and 32.2% neither PTEN nor PHLPP phosphatases. Compared to nucleophosmin mutation (NPMc) negative samples P-Erk was significantly less in nucleophosmin mutated patients, P-Rb was significantly less in patients' group with more than 30 G/L peripheral leukocyte count by diagnosis. PHLPP was significantly present in FAB type M5. The expression of P-Rb represented significant better overall survival (OS), while P-Akt represented significantly worse event-free survival (EFS) in unfavorable cytogenetics patients. The presence of both PHLPP and PTEN phosphatases contributes to better OS and EFS, although the differences were not statistically significant. We confirmed significant positive correlation between P-Akt and PHLPP. Assessing the phosphorylation of Rb, Akt and Erk may define a subgroup of AML patients who would benefit especially from new targeted treatment options complemented the standard chemotherapy, and it may contribute to monitoring remission, relapse or progression of AML.
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Affiliation(s)
- Adrienn Márton
- Division of Hematology, Department of Internal Medicine, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
- Kálmán Laki Doctoral School, University of Debrecen, Debrecen, Hungary
| | | | - Ferenc Erdődi
- Department of Medical Chemistry, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - Miklós Udvardy
- Division of Hematology, Department of Internal Medicine, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - Árpád Illés
- Division of Hematology, Department of Internal Medicine, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - László Rejtő
- Department of Hematology, Szabolcs-Szatmár-Bereg County Teaching Hospital, Nyíregyháza, Hungary
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Huang D, Yu Z, Lu H, Jiang P, Qian X, Han Y, Qian P. Adhesion GPCR ADGRE2 Maintains Proteostasis to Promote Progression in Acute Myeloid Leukemia. Cancer Res 2024; 84:2090-2108. [PMID: 39082681 DOI: 10.1158/0008-5472.can-23-2314] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2023] [Revised: 01/19/2024] [Accepted: 03/28/2024] [Indexed: 08/15/2024]
Abstract
Acute myeloid leukemia (AML) is an aggressive and heterogeneous hematologic malignancy. In elderly patients, AML incidence is high and has a poor prognosis due to a lack of effective therapies. G protein-coupled receptors (GPCR) play integral roles in physiologic processes and human diseases. Particularly, one third of adhesion GPCRs, the second largest group of GPCRs, are highly expressed in hematopoietic stem and progenitor cells or lineage cells. Here, we investigate the role of adhesion GPCRs in AML and whether they could be harnessed as antileukemia targets. Systematic screening of the impact of adhesion GPCRs on AML functionality by bioinformatic and functional analyses revealed high expression of ADGRE2 in AML, particularly in leukemic stem cells, which is associated with poor patient outcomes. Silencing ADGRE2 not only exerts antileukemic effects in AML cell lines and cells derived from patients with AML in vitro, but also delays AML progression in xenograft models in vivo. Mechanistically, ADGRE2 activates phospholipase Cβ/protein kinase C/MEK/ERK signaling to enhance the expression of AP1 and transcriptionally drive the expression of DUSP1, a protein phosphatase. DUSP1 dephosphorylates Ser16 in the J-domain of the co-chaperone DNAJB1, which facilitates the DNAJB1-HSP70 interaction and maintenance of proteostasis in AML. Finally, combined inhibition of MEK, AP1, and DUSP1 exhibits robust therapeutic efficacy in AML xenograft mouse models. Collectively, this study deciphers the roles and mechanisms of ADGRE2 in AML and provides a promising therapeutic strategy for treating AML. Significance: Increased expression of the adhesion GPCR member ADGRE2 in AML supports leukemia stem cell self-renewal and leukemogenesis by modulating proteostasis via an MEK/AP1/DUSP1 axis, which can be targeted to suppress AML progression.
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MESH Headings
- Animals
- Humans
- Mice
- Cell Line, Tumor
- Cell Proliferation
- Disease Progression
- Leukemia, Myeloid, Acute/pathology
- Leukemia, Myeloid, Acute/metabolism
- Leukemia, Myeloid, Acute/genetics
- Mice, Inbred NOD
- Neoplastic Stem Cells/metabolism
- Neoplastic Stem Cells/pathology
- Proteostasis
- Receptors, G-Protein-Coupled/metabolism
- Receptors, G-Protein-Coupled/genetics
- Xenograft Model Antitumor Assays
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Affiliation(s)
- Deyu Huang
- Bone Marrow Transplantation Center of the First Affiliated Hospital, Center for Stem Cell and Regenerative Medicine, Zhejiang University School of Medicine, Hangzhou, China
- Liangzhu Laboratory, Zhejiang University, Hangzhou, China
- State Key Laboratory of Experimental Hematology, Institute of Hematology, Zhejiang University and Zhejiang Provincial Engineering Research Center for Stem Cell and Immunity Therapy, Hangzhou, China
| | - Zebin Yu
- Bone Marrow Transplantation Center of the First Affiliated Hospital, Center for Stem Cell and Regenerative Medicine, Zhejiang University School of Medicine, Hangzhou, China
- Liangzhu Laboratory, Zhejiang University, Hangzhou, China
- State Key Laboratory of Experimental Hematology, Institute of Hematology, Zhejiang University and Zhejiang Provincial Engineering Research Center for Stem Cell and Immunity Therapy, Hangzhou, China
| | - Huan Lu
- Bone Marrow Transplantation Center of the First Affiliated Hospital, Center for Stem Cell and Regenerative Medicine, Zhejiang University School of Medicine, Hangzhou, China
- Liangzhu Laboratory, Zhejiang University, Hangzhou, China
- State Key Laboratory of Experimental Hematology, Institute of Hematology, Zhejiang University and Zhejiang Provincial Engineering Research Center for Stem Cell and Immunity Therapy, Hangzhou, China
| | - Penglei Jiang
- Bone Marrow Transplantation Center of the First Affiliated Hospital, Center for Stem Cell and Regenerative Medicine, Zhejiang University School of Medicine, Hangzhou, China
- Liangzhu Laboratory, Zhejiang University, Hangzhou, China
- State Key Laboratory of Experimental Hematology, Institute of Hematology, Zhejiang University and Zhejiang Provincial Engineering Research Center for Stem Cell and Immunity Therapy, Hangzhou, China
| | - Xinyue Qian
- Bone Marrow Transplantation Center of the First Affiliated Hospital, Center for Stem Cell and Regenerative Medicine, Zhejiang University School of Medicine, Hangzhou, China
- Liangzhu Laboratory, Zhejiang University, Hangzhou, China
- State Key Laboratory of Experimental Hematology, Institute of Hematology, Zhejiang University and Zhejiang Provincial Engineering Research Center for Stem Cell and Immunity Therapy, Hangzhou, China
| | - Yingli Han
- Bone Marrow Transplantation Center of the First Affiliated Hospital, Center for Stem Cell and Regenerative Medicine, Zhejiang University School of Medicine, Hangzhou, China
- Liangzhu Laboratory, Zhejiang University, Hangzhou, China
| | - Pengxu Qian
- Bone Marrow Transplantation Center of the First Affiliated Hospital, Center for Stem Cell and Regenerative Medicine, Zhejiang University School of Medicine, Hangzhou, China
- Liangzhu Laboratory, Zhejiang University, Hangzhou, China
- State Key Laboratory of Experimental Hematology, Institute of Hematology, Zhejiang University and Zhejiang Provincial Engineering Research Center for Stem Cell and Immunity Therapy, Hangzhou, China
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Ye G, Wang J, Xia J, Zhu C, Gu C, Li X, Li J, Ye M, Jin X. Low protein expression of LZTR1 in hepatocellular carcinoma triggers tumorigenesis via activating the RAS/RAF/MEK/ERK signaling. Heliyon 2024; 10:e32855. [PMID: 38994114 PMCID: PMC11237970 DOI: 10.1016/j.heliyon.2024.e32855] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2023] [Revised: 06/10/2024] [Accepted: 06/11/2024] [Indexed: 07/13/2024] Open
Abstract
LZTR1 is a substrate specific adaptor for E3 ligase involved in the ubiquitination and degradation of RAS GTPases, which inhibits the RAS/RAF/MEK/ERK signaling to suppress the pathogenesis of Noonan syndrome and glioblastoma. However, it's still unknown whether LZTR1 destabilizes RAS GTPases to suppress HCC progression by inhibiting these signaling pathway. Lenvatinib is the first-line drug for the treatment of advanced HCC, however, it has high drug resistance. To explore the roles of LZTR1 in HCC progression and the underlying mechanisms of lenvatinib resistance, techniques such as bioinformatics analysis, immunohistochemical staining, RT-qPCR, Western blot, cell functional experiments, small interfering RNA transfection and cycloheximide chase assay were applied in our study. Among these, bioinformatics analysis and immunohistochemical staining results indicated that LZTR1 protein was aberrantly expressed at low levels in HCC tissues, and low protein expression of LZTR1 was associated with poor prognosis of HCC patients. In vitro functional experiments confirmed that low expression of LZTR1 promoted HCC cell proliferation and migration via the aberrant activation of the RAS/RAF/MEK/ERK signaling due to the dysregulation of LZTR1-induced KRAS ubiquitination and degradation. Transwell assays revealed that blocking of LZTR1-mediated KRAS degradation could induce lenvatinib resistance in HCC cells. In conclusion, our study revealed that LZTR1 knockdown promoted HCC cell proliferation and migration, and induced lenvatinib resistance via activating the RAS/RAF/MEK/ERK signaling, which may provide new ideas for HCC treatment.
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Affiliation(s)
- Ganghui Ye
- Department of Biochemistry and Molecular Biology, Health Science Center, Ningbo University, Ningbo, 315211, China
- Department of Oncology, The First Hospital of Ningbo University, Ningbo, 315020, China
| | - Jie Wang
- Department of Biochemistry and Molecular Biology, Health Science Center, Ningbo University, Ningbo, 315211, China
- Department of Oncology, The First Hospital of Ningbo University, Ningbo, 315020, China
| | - Jingyi Xia
- Zhejiang Key Laboratory of Pathophysiology, Department of Biochemistry and Molecular Biology, Health Science Center of Ningbo University, Ningbo, 315211, China
| | - Chenlu Zhu
- Zhejiang Key Laboratory of Pathophysiology, Department of Biochemistry and Molecular Biology, Health Science Center of Ningbo University, Ningbo, 315211, China
| | - Chaoyu Gu
- Department of Oncology, The First Hospital of Ningbo University, Ningbo, 315020, China
| | - Xinming Li
- Department of Oncology, The First Hospital of Ningbo University, Ningbo, 315020, China
| | - Jingyun Li
- Department of Biochemistry and Molecular Biology, Health Science Center, Ningbo University, Ningbo, 315211, China
- Department of Oncology, The First Hospital of Ningbo University, Ningbo, 315020, China
| | - Meng Ye
- Department of Biochemistry and Molecular Biology, Health Science Center, Ningbo University, Ningbo, 315211, China
- Department of Oncology, The First Hospital of Ningbo University, Ningbo, 315020, China
| | - Xiaofeng Jin
- Department of Biochemistry and Molecular Biology, Health Science Center, Ningbo University, Ningbo, 315211, China
- Department of Oncology, The First Hospital of Ningbo University, Ningbo, 315020, China
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Zhou Y, Tao L, Qiu J, Xu J, Yang X, Zhang Y, Tian X, Guan X, Cen X, Zhao Y. Tumor biomarkers for diagnosis, prognosis and targeted therapy. Signal Transduct Target Ther 2024; 9:132. [PMID: 38763973 PMCID: PMC11102923 DOI: 10.1038/s41392-024-01823-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2023] [Revised: 03/07/2024] [Accepted: 04/02/2024] [Indexed: 05/21/2024] Open
Abstract
Tumor biomarkers, the substances which are produced by tumors or the body's responses to tumors during tumorigenesis and progression, have been demonstrated to possess critical and encouraging value in screening and early diagnosis, prognosis prediction, recurrence detection, and therapeutic efficacy monitoring of cancers. Over the past decades, continuous progress has been made in exploring and discovering novel, sensitive, specific, and accurate tumor biomarkers, which has significantly promoted personalized medicine and improved the outcomes of cancer patients, especially advances in molecular biology technologies developed for the detection of tumor biomarkers. Herein, we summarize the discovery and development of tumor biomarkers, including the history of tumor biomarkers, the conventional and innovative technologies used for biomarker discovery and detection, the classification of tumor biomarkers based on tissue origins, and the application of tumor biomarkers in clinical cancer management. In particular, we highlight the recent advancements in biomarker-based anticancer-targeted therapies which are emerging as breakthroughs and promising cancer therapeutic strategies. We also discuss limitations and challenges that need to be addressed and provide insights and perspectives to turn challenges into opportunities in this field. Collectively, the discovery and application of multiple tumor biomarkers emphasized in this review may provide guidance on improved precision medicine, broaden horizons in future research directions, and expedite the clinical classification of cancer patients according to their molecular biomarkers rather than organs of origin.
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Affiliation(s)
- Yue Zhou
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Lei Tao
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Jiahao Qiu
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Jing Xu
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Xinyu Yang
- West China School of Pharmacy, Sichuan University, Chengdu, 610041, China
| | - Yu Zhang
- West China School of Pharmacy, Sichuan University, Chengdu, 610041, China
- School of Medicine, Tibet University, Lhasa, 850000, China
| | - Xinyu Tian
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Xinqi Guan
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Xiaobo Cen
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
- National Chengdu Center for Safety Evaluation of Drugs, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Yinglan Zhao
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China.
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Modak RV, de Oliveira Rebola KG, McClatchy J, Mohammadhosseini M, Damnernsawad A, Kurtz SE, Eide CA, Wu G, Laderas T, Nechiporuk T, Gritsenko MA, Hansen JR, Hutchinson C, Gosline SJ, Piehowski P, Bottomly D, Short N, Rodland K, McWeeney SK, Tyner JW, Agarwal A. Targeting CCL2/CCR2 Signaling Overcomes MEK Inhibitor Resistance in Acute Myeloid Leukemia. Clin Cancer Res 2024; 30:2245-2259. [PMID: 38451486 PMCID: PMC11094423 DOI: 10.1158/1078-0432.ccr-23-2654] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2023] [Revised: 12/29/2023] [Accepted: 03/05/2024] [Indexed: 03/08/2024]
Abstract
PURPOSE Emerging evidence underscores the critical role of extrinsic factors within the microenvironment in protecting leukemia cells from therapeutic interventions, driving disease progression, and promoting drug resistance in acute myeloid leukemia (AML). This finding emphasizes the need for the identification of targeted therapies that inhibit intrinsic and extrinsic signaling to overcome drug resistance in AML. EXPERIMENTAL DESIGN We performed a comprehensive analysis utilizing a cohort of ∼300 AML patient samples. This analysis encompassed the evaluation of secreted cytokines/growth factors, gene expression, and ex vivo drug sensitivity to small molecules. Our investigation pinpointed a notable association between elevated levels of CCL2 and diminished sensitivity to the MEK inhibitors (MEKi). We validated this association through loss-of-function and pharmacologic inhibition studies. Further, we deployed global phosphoproteomics and CRISPR/Cas9 screening to identify the mechanism of CCR2-mediated MEKi resistance in AML. RESULTS Our multifaceted analysis unveiled that CCL2 activates multiple prosurvival pathways, including MAPK and cell-cycle regulation in MEKi-resistant cells. Employing combination strategies to simultaneously target these pathways heightened growth inhibition in AML cells. Both genetic and pharmacologic inhibition of CCR2 sensitized AML cells to trametinib, suppressing proliferation while enhancing apoptosis. These findings underscore a new role for CCL2 in MEKi resistance, offering combination therapies as an avenue to circumvent this resistance. CONCLUSIONS Our study demonstrates a compelling rationale for translating CCL2/CCR2 axis inhibitors in combination with MEK pathway-targeting therapies, as a potent strategy for combating drug resistance in AML. This approach has the potential to enhance the efficacy of treatments to improve AML patient outcomes.
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MESH Headings
- Humans
- Leukemia, Myeloid, Acute/drug therapy
- Leukemia, Myeloid, Acute/genetics
- Leukemia, Myeloid, Acute/metabolism
- Leukemia, Myeloid, Acute/pathology
- Receptors, CCR2/metabolism
- Receptors, CCR2/antagonists & inhibitors
- Receptors, CCR2/genetics
- Drug Resistance, Neoplasm/genetics
- Chemokine CCL2/metabolism
- Chemokine CCL2/genetics
- Protein Kinase Inhibitors/pharmacology
- Protein Kinase Inhibitors/therapeutic use
- Signal Transduction/drug effects
- Cell Line, Tumor
- Cell Proliferation/drug effects
- Animals
- Pyridones/pharmacology
- Pyridones/therapeutic use
- Mice
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Affiliation(s)
- Rucha V. Modak
- Division of Oncological Sciences, Oregon Health & Science University, Portland, Oregon
- Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon
- Department of Molecular and Medical Genetics, Oregon Health & Science University, Portland, Oregon
- Department of Cell, Developmental, & Cancer Biology, Oregon Health & Science University, Portland, Oregon
| | - Katia G. de Oliveira Rebola
- Division of Oncological Sciences, Oregon Health & Science University, Portland, Oregon
- Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon
- Department of Molecular and Medical Genetics, Oregon Health & Science University, Portland, Oregon
- Department of Cell, Developmental, & Cancer Biology, Oregon Health & Science University, Portland, Oregon
| | - John McClatchy
- Division of Oncological Sciences, Oregon Health & Science University, Portland, Oregon
- Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon
- Department of Molecular and Medical Genetics, Oregon Health & Science University, Portland, Oregon
- Department of Cell, Developmental, & Cancer Biology, Oregon Health & Science University, Portland, Oregon
| | - Mona Mohammadhosseini
- Division of Oncological Sciences, Oregon Health & Science University, Portland, Oregon
- Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon
- Department of Molecular and Medical Genetics, Oregon Health & Science University, Portland, Oregon
- Department of Cell, Developmental, & Cancer Biology, Oregon Health & Science University, Portland, Oregon
| | - Alisa Damnernsawad
- Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon
- Department of Cell, Developmental, & Cancer Biology, Oregon Health & Science University, Portland, Oregon
- Department of Biology, Faculty of Science, Mahidol University, Bangkok, Thailand
| | - Stephen E. Kurtz
- Division of Oncological Sciences, Oregon Health & Science University, Portland, Oregon
- Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon
- Department of Cell, Developmental, & Cancer Biology, Oregon Health & Science University, Portland, Oregon
| | - Christopher A. Eide
- Division of Oncological Sciences, Oregon Health & Science University, Portland, Oregon
- Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon
| | - Guanming Wu
- Division of Bioinformatics & Computational Biology, Oregon Health & Science University, Portland, Oregon
| | - Ted Laderas
- Division of Bioinformatics & Computational Biology, Oregon Health & Science University, Portland, Oregon
| | - Tamilla Nechiporuk
- Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon
- Department of Cell, Developmental, & Cancer Biology, Oregon Health & Science University, Portland, Oregon
| | | | | | | | - Sara J.C. Gosline
- Pacific Northwest National Laboratory, Richland, Washington
- Department of Biomedical Engineering, School of Medicine, Oregon Health & Science University, Portland, Oregon
| | - Paul Piehowski
- Pacific Northwest National Laboratory, Richland, Washington
| | - Daniel Bottomly
- Division of Bioinformatics & Computational Biology, Oregon Health & Science University, Portland, Oregon
| | - Nicholas Short
- Department of Leukemia, MD Anderson Cancer Center, Houston, Texas
| | - Karin Rodland
- Pacific Northwest National Laboratory, Richland, Washington
| | - Shannon K. McWeeney
- Division of Bioinformatics & Computational Biology, Oregon Health & Science University, Portland, Oregon
| | - Jeffrey W. Tyner
- Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon
- Department of Cell, Developmental, & Cancer Biology, Oregon Health & Science University, Portland, Oregon
| | - Anupriya Agarwal
- Division of Oncological Sciences, Oregon Health & Science University, Portland, Oregon
- Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon
- Department of Molecular and Medical Genetics, Oregon Health & Science University, Portland, Oregon
- Department of Cell, Developmental, & Cancer Biology, Oregon Health & Science University, Portland, Oregon
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Macečková D, Vaňková L, Holubová M, Jindra P, Klieber R, Jandová E, Pitule P. Current knowledge about FLT3 gene mutations, exploring the isoforms, and protein importance in AML. Mol Biol Rep 2024; 51:521. [PMID: 38625438 DOI: 10.1007/s11033-024-09452-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2024] [Accepted: 03/15/2024] [Indexed: 04/17/2024]
Abstract
Acute myeloid leukaemia (AML) is a complex haematological malignancy characterised by diverse genetic alterations leading to abnormal proliferation of myeloid precursor cells. One of the most significant genetic alterations in AML involves mutations in the FLT3 gene, which plays a critical role in haematopoiesis and haematopoietic homeostasis. This review explores the current understanding of FLT3 gene mutations and isoforms and the importance of the FLT3 protein in AML. FLT3 mutations, including internal tandem duplications (FLT3-ITD) and point mutations in the tyrosine kinase domain (FLT3-TKD), occur in 25-30% in AML and are associated with poor prognosis. FLT3-ITD mutations lead to constitutive activation of the FLT3 signalling pathway, promoting cell survival and proliferation. FLT3-TKD mutations affect the tyrosine kinase domain and affect AML prognosis in various ways. Furthermore, FLT3 isoforms, including shorter variants, contribute to the complexity of FLT3 biology. Additionally, nonpathological polymorphisms in FLT3 are being explored for their potential impact on AML prognosis and treatment response. This review also discusses the development of molecular treatments targeting FLT3, including first-generation and next-generation tyrosine kinase inhibitors, highlighting the challenges of resistance that often arise during therapy. The final chapter describes FLT3 protein domain rearrangements and their relevance to AML pathogenesis.
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Affiliation(s)
- Diana Macečková
- Laboratory of Tumor Biology and Immunotherapy Biomedical Center, Faculty of Medicine in Pilsen, Charles University, Alej Svobody 76, Pilsen, 32300, Czechia.
| | - Lenka Vaňková
- Department of Histology and Embryology, Faculty of Medicine in Pilsen, Charles University, Pilsen, Czechia
| | - Monika Holubová
- Laboratory of Tumor Biology and Immunotherapy Biomedical Center, Faculty of Medicine in Pilsen, Charles University, Alej Svobody 76, Pilsen, 32300, Czechia
- Department of Haematology and Oncology, University Hospital Pilsen, Pilsen, Czechia
| | - Pavel Jindra
- Department of Haematology and Oncology, University Hospital Pilsen, Pilsen, Czechia
| | - Robin Klieber
- Laboratory of Tumor Biology and Immunotherapy Biomedical Center, Faculty of Medicine in Pilsen, Charles University, Alej Svobody 76, Pilsen, 32300, Czechia
- Department of Haematology and Oncology, University Hospital Pilsen, Pilsen, Czechia
| | - Eliška Jandová
- Laboratory of Tumor Biology and Immunotherapy Biomedical Center, Faculty of Medicine in Pilsen, Charles University, Alej Svobody 76, Pilsen, 32300, Czechia
| | - Pavel Pitule
- Laboratory of Tumor Biology and Immunotherapy Biomedical Center, Faculty of Medicine in Pilsen, Charles University, Alej Svobody 76, Pilsen, 32300, Czechia
- Department of Histology and Embryology, Faculty of Medicine in Pilsen, Charles University, Pilsen, Czechia
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9
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Wang C, Wang B, Mou Y, Liu X, Chen Q, Pu W, Rao Q, Wang C, Song J, Huang Y, Yan L, Huang L, Li Y. Design, Synthesis, and Anti-Leukemic Evaluation of a Series of Dianilinopyrimidines by Regulating the Ras/Raf/MEK/ERK and STAT3/c-Myc Pathways. Molecules 2024; 29:1597. [PMID: 38611876 PMCID: PMC11013136 DOI: 10.3390/molecules29071597] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2023] [Revised: 03/17/2024] [Accepted: 03/19/2024] [Indexed: 04/14/2024] Open
Abstract
Although the long-term survival rate for leukemia has made significant progress over the years with the development of chemotherapeutics, patients still suffer from relapse, leading to an unsatisfactory outcome. To discover the new effective anti-leukemia compounds, we synthesized a series of dianilinopyrimidines and evaluated the anti-leukemia activities of those compounds by using leukemia cell lines (HEL, Jurkat, and K562). The results showed that the dianilinopyrimidine analog H-120 predominantly displayed the highest cytotoxic potential in HEL cells. It remarkably induced apoptosis of HEL cells by activating the apoptosis-related proteins (cleaved caspase-3, cleaved caspase-9 and cleaved poly ADP-ribose polymerase (PARP)), increasing apoptosis protein Bad expression, and decreasing the expression of anti-apoptotic proteins (Bcl-2 and Bcl-xL). Furthermore, it induced cell cycle arrest in G2/M; concomitantly, we observed the activation of p53 and a reduction in phosphorylated cell division cycle 25C (p-CDC25C) / Cyclin B1 levels in treated cells. Additionally, the mechanism study revealed that H-120 decreased these phosphorylated signal transducers and activators of transcription 3, rat sarcoma, phosphorylated cellular RAF proto-oncogene serine / threonine kinase, phosphorylated mitogen-activated protein kinase kinase, phosphorylated extracellular signal-regulated kinase, and cellular myelocytomatosis oncogene (p-STAT3, Ras, p-C-Raf, p-MEK, p-MRK, and c-Myc) protein levels in HEL cells. Using the cytoplasmic and nuclear proteins isolation assay, we found for the first time that H-120 can inhibit the activation of STAT3 and c-Myc and block STAT3 phosphorylation and dimerization. Moreover, H-120 treatment effectively inhibited the disease progression of erythroleukemia mice by promoting erythroid differentiation into the maturation of erythrocytes and activating the immune cells. Significantly, H-120 also improved liver function in erythroleukemia mice. Therefore, H-120 may be a potential chemotherapeutic drug for leukemia patients.
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Affiliation(s)
- Chaoyan Wang
- State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang 550014, China; (C.W.); (B.W.); (Y.M.); (X.L.); (Q.C.); (W.P.); (Q.R.); (C.W.); (J.S.); (Y.H.)
- Natural Products Research Center of Guizhou Province, Guiyang 550014, China
- College of Pharmacy, Guizhou Medical University, Guiyang 550004, China
| | - Bo Wang
- State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang 550014, China; (C.W.); (B.W.); (Y.M.); (X.L.); (Q.C.); (W.P.); (Q.R.); (C.W.); (J.S.); (Y.H.)
- Natural Products Research Center of Guizhou Province, Guiyang 550014, China
- College of Basic Medical, Guizhou Medical University, Guiyang 550004, China
| | - Yu Mou
- State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang 550014, China; (C.W.); (B.W.); (Y.M.); (X.L.); (Q.C.); (W.P.); (Q.R.); (C.W.); (J.S.); (Y.H.)
- Natural Products Research Center of Guizhou Province, Guiyang 550014, China
- College of Pharmacy, Guizhou Medical University, Guiyang 550004, China
| | - Xiang Liu
- State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang 550014, China; (C.W.); (B.W.); (Y.M.); (X.L.); (Q.C.); (W.P.); (Q.R.); (C.W.); (J.S.); (Y.H.)
- Natural Products Research Center of Guizhou Province, Guiyang 550014, China
- College of Basic Medical, Guizhou Medical University, Guiyang 550004, China
| | - Qiqing Chen
- State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang 550014, China; (C.W.); (B.W.); (Y.M.); (X.L.); (Q.C.); (W.P.); (Q.R.); (C.W.); (J.S.); (Y.H.)
- Natural Products Research Center of Guizhou Province, Guiyang 550014, China
- College of Pharmacy, Guizhou Medical University, Guiyang 550004, China
| | - Weidong Pu
- State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang 550014, China; (C.W.); (B.W.); (Y.M.); (X.L.); (Q.C.); (W.P.); (Q.R.); (C.W.); (J.S.); (Y.H.)
- Natural Products Research Center of Guizhou Province, Guiyang 550014, China
- College of Pharmacy, Guizhou Medical University, Guiyang 550004, China
| | - Qing Rao
- State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang 550014, China; (C.W.); (B.W.); (Y.M.); (X.L.); (Q.C.); (W.P.); (Q.R.); (C.W.); (J.S.); (Y.H.)
- Natural Products Research Center of Guizhou Province, Guiyang 550014, China
| | - Chunlin Wang
- State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang 550014, China; (C.W.); (B.W.); (Y.M.); (X.L.); (Q.C.); (W.P.); (Q.R.); (C.W.); (J.S.); (Y.H.)
- Natural Products Research Center of Guizhou Province, Guiyang 550014, China
| | - Jingrui Song
- State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang 550014, China; (C.W.); (B.W.); (Y.M.); (X.L.); (Q.C.); (W.P.); (Q.R.); (C.W.); (J.S.); (Y.H.)
- Natural Products Research Center of Guizhou Province, Guiyang 550014, China
| | - Yubing Huang
- State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang 550014, China; (C.W.); (B.W.); (Y.M.); (X.L.); (Q.C.); (W.P.); (Q.R.); (C.W.); (J.S.); (Y.H.)
- Natural Products Research Center of Guizhou Province, Guiyang 550014, China
| | - Longjia Yan
- School of Pharmaceutical Sciences, Guizhou University, Guiyang 550000, China
| | - Lei Huang
- State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang 550014, China; (C.W.); (B.W.); (Y.M.); (X.L.); (Q.C.); (W.P.); (Q.R.); (C.W.); (J.S.); (Y.H.)
- Natural Products Research Center of Guizhou Province, Guiyang 550014, China
| | - Yanmei Li
- State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang 550014, China; (C.W.); (B.W.); (Y.M.); (X.L.); (Q.C.); (W.P.); (Q.R.); (C.W.); (J.S.); (Y.H.)
- Natural Products Research Center of Guizhou Province, Guiyang 550014, China
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Liao B, Wang J, Yuan Y, Luo H, Ouyang X. Biological roles of SLC16A1-AS1 lncRNA and its clinical impacts in tumors. Cancer Cell Int 2024; 24:122. [PMID: 38555465 PMCID: PMC10981830 DOI: 10.1186/s12935-024-03285-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2023] [Accepted: 02/27/2024] [Indexed: 04/02/2024] Open
Abstract
Recent studies have increasingly highlighted the aberrant expression of SLC16A1-AS1 in a variety of tumor types, where it functions as either an oncogene or a tumor suppressor in the pathogenesis of different cancers. The expression levels of SLC16A1-AS1 have been found to significantly correlate with clinical features and the prognosis of cancer patients. Furthermore, SLC16A1-AS1 modulates a range of cellular functions, including proliferation, migration, and invasion, through its interactions with diverse molecules and signaling pathways. This review examines the latest evidence regarding the role of SLC16A1-AS1 in the progression of various tumors and explores its potential clinical applications as a novel prognostic and diagnostic biomarker. Our comprehensive review aims to deepen the understanding of SLC16A1-AS1's multifaceted role in oncology, underscoring its potential as a significant biomarker and therapeutic target.
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Affiliation(s)
- Bing Liao
- Department of Otorhinolaryngology, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, 330008, Jiangxi, China
| | - Jialing Wang
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, 330008, Jiangxi, China
| | - Yalin Yuan
- Second School of Clinical Medicine, Jiangxi Medical College, Nanchang University, Nanchang, 330008, Jiangxi, China
| | - Hongliang Luo
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, 330008, Jiangxi, China
| | - Xi Ouyang
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, 330008, Jiangxi, China.
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11
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Mirzaie M, Gholizadeh E, Miettinen JJ, Ianevski F, Ruokoranta T, Saarela J, Manninen M, Miettinen S, Heckman CA, Jafari M. Designing patient-oriented combination therapies for acute myeloid leukemia based on efficacy/toxicity integration and bipartite network modeling. Oncogenesis 2024; 13:11. [PMID: 38429288 PMCID: PMC10907624 DOI: 10.1038/s41389-024-00510-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2023] [Revised: 02/01/2024] [Accepted: 02/06/2024] [Indexed: 03/03/2024] Open
Abstract
Acute myeloid leukemia (AML), a heterogeneous and aggressive blood cancer, does not respond well to single-drug therapy. A combination of drugs is required to effectively treat this disease. Computational models are critical for combination therapy discovery due to the tens of thousands of two-drug combinations, even with approved drugs. While predicting synergistic drugs is the focus of current methods, few consider drug efficacy and potential toxicity, which are crucial for treatment success. To find effective new drug candidates, we constructed a bipartite network using patient-derived tumor samples and drugs. The network is based on drug-response screening and summarizes all treatment response heterogeneity as drug response weights. This bipartite network is then projected onto the drug part, resulting in the drug similarity network. Distinct drug clusters were identified using community detection methods, each targeting different biological processes and pathways as revealed by enrichment and pathway analysis of the drugs' protein targets. Four drugs with the highest efficacy and lowest toxicity from each cluster were selected and tested for drug sensitivity using cell viability assays on various samples. Results show that ruxolitinib-ulixertinib and sapanisertib-LY3009120 are the most effective combinations with the least toxicity and the best synergistic effect on blast cells. These findings lay the foundation for personalized and successful AML therapies, ultimately leading to the development of drug combinations that can be used alongside standard first-line AML treatment.
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Affiliation(s)
- Mehdi Mirzaie
- Department of Biochemistry and Developmental Biology, University of Helsinki, Helsinki, Finland
| | - Elham Gholizadeh
- Department of Biochemistry and Developmental Biology, University of Helsinki, Helsinki, Finland
| | - Juho J Miettinen
- Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, Helsinki, Finland
| | - Filipp Ianevski
- Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, Helsinki, Finland
| | - Tanja Ruokoranta
- Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, Helsinki, Finland
- Department of Hematology, Helsinki University Hospital Comprehensive Cancer Center, Helsinki, Finland
| | - Jani Saarela
- Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, Helsinki, Finland
| | | | - Susanna Miettinen
- Adult Stem Cell Group, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
- Tays Research Services, Wellbeing Services County of Pirkanmaa, Tampere University Hospital, Tampere, Finland
| | - Caroline A Heckman
- Institute for Molecular Medicine Finland - FIMM, HiLIFE - Helsinki Institute of Life Science, iCAN Digital Precision Cancer Medicine Flagship, University of Helsinki, Helsinki, Finland.
| | - Mohieddin Jafari
- Department of Biochemistry and Developmental Biology, University of Helsinki, Helsinki, Finland.
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12
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Wang B, Wang M, Li K, Wang C, Liu X, Rao Q, Song J, Hang Y, Liu S, Wen M, Huang L, Li Y. Calothrixin B derivatives induce apoptosis and cell cycle arrest on HEL cells through the ERK/Ras/Raf/MEK pathway. Biomed Pharmacother 2024; 171:116179. [PMID: 38278023 DOI: 10.1016/j.biopha.2024.116179] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2023] [Revised: 01/06/2024] [Accepted: 01/16/2024] [Indexed: 01/28/2024] Open
Abstract
BACKGROUND Acute erythroleukemia (AEL) is acute myeloid leukemia characterized by malignant erythroid proliferation. AEL has a low survival rate, which has seriously threatened the health of older adults. Calothrixin B is a carbazole alkaloid isolated from the cyanobacteria Calothrix and exhibits anti-cancer activity. To discover more potential anti-erythroleukemia compounds, we used calothrixin B as the structural skeleton to synthesize a series of new compounds. METHODS In the cell culture model, we evaluated apoptosis and cell cycle arrest using MTT assay, flow cytometry analysis, JC-1 staining, Hoechst 33258 staining, and Western blot. Additionally, assessing the curative effect in the animal model included observation of the spleen, HE staining, flow cytometry analysis, and detection of serum biochemical indexes. RESULTS Among the Calothrixin B derivatives, H-107 had the best activity against leukemic cell lines. H-107 significantly inhibited the proliferation of HEL cells with an IC50 value of 3.63 ± 0.33 μM. H-107 induced apoptosis of HEL cells by damaging mitochondria and activating the caspase cascade and arrested HEL cells in the G0/G1 phase. Furthermore, H-107 downregulated the protein levels Ras, p-Raf, p-MEK, p-ERK and c-Myc. Pretreatment with ERK inhibitor (U0126) increased H-107-induced apoptosis. Thus, H-107 inhibited the proliferation of HEL cells by the ERK /Ras/Raf/MEK signal pathways. Interestingly, H-107 promoted erythroid differentiation into the maturation of erythrocytes and effectively activated the immune cells in erythroleukemia mice. CONCLUSION Overall, our findings suggest that H-107 can potentially be a novel chemotherapy for erythroleukemia.
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Affiliation(s)
- Bo Wang
- State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang 550014, China; Natural Products Research Center of Guizhou Province, Guiyang 550014, China; College of Basic Medical, Guizhou Medical University, Guizhou 550004, China
| | - Ming Wang
- State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang 550014, China; Natural Products Research Center of Guizhou Province, Guiyang 550014, China; College of Pharmacy, Guizhou Medical University, Guizhou 550004, China
| | - Ke Li
- State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang 550014, China; Natural Products Research Center of Guizhou Province, Guiyang 550014, China
| | - Chaoyan Wang
- State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang 550014, China; Natural Products Research Center of Guizhou Province, Guiyang 550014, China; College of Pharmacy, Guizhou Medical University, Guizhou 550004, China
| | - Xiang Liu
- State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang 550014, China; Natural Products Research Center of Guizhou Province, Guiyang 550014, China; College of Basic Medical, Guizhou Medical University, Guizhou 550004, China
| | - Qing Rao
- State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang 550014, China; Natural Products Research Center of Guizhou Province, Guiyang 550014, China
| | - Jingrui Song
- State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang 550014, China; Natural Products Research Center of Guizhou Province, Guiyang 550014, China
| | - Yubing Hang
- State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang 550014, China; Natural Products Research Center of Guizhou Province, Guiyang 550014, China
| | - Sheng Liu
- State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang 550014, China; Natural Products Research Center of Guizhou Province, Guiyang 550014, China.
| | - Min Wen
- State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang 550014, China; Guizhou Provincial Engineering Technology Research Center for Chemical Drug R&D, Guizhou Medical University, Guizhou 550004, China; College of Basic Medical, Guizhou Medical University, Guizhou 550004, China; College of Pharmacy, Guizhou Medical University, Guizhou 550004, China.
| | - Lei Huang
- State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang 550014, China; Natural Products Research Center of Guizhou Province, Guiyang 550014, China.
| | - Yanmei Li
- State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang 550014, China; Natural Products Research Center of Guizhou Province, Guiyang 550014, China.
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13
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Wang H, Sica RA, Kaur G, Galbo PM, Jing Z, Nishimura CD, Ren X, Tanwar A, Etemad-Gilbertson B, Will B, Zheng D, Fooksman D, Zang X. TMIGD2 is an orchestrator and therapeutic target on human acute myeloid leukemia stem cells. Nat Commun 2024; 15:11. [PMID: 38167704 PMCID: PMC10761673 DOI: 10.1038/s41467-023-43843-6] [Citation(s) in RCA: 7] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2022] [Accepted: 11/21/2023] [Indexed: 01/05/2024] Open
Abstract
Acute myeloid leukemia (AML) is initiated and sustained by a hierarchy of leukemia stem cells (LSCs), and elimination of this cell population is required for curative therapies. Here we show that transmembrane and immunoglobulin domain containing 2 (TMIGD2), a recently discovered co-stimulatory immune receptor, is aberrantly expressed by human AML cells, and can be used to identify and enrich functional LSCs. We demonstrate that TMIGD2 is required for the development and maintenance of AML and self-renewal of LSCs but is not essential for normal hematopoiesis. Mechanistically, TMIGD2 promotes proliferation, blocks myeloid differentiation and increases cell-cycle of AML cells via an ERK1/2-p90RSK-CREB signaling axis. Targeting TMIGD2 signaling with anti-TMIGD2 monoclonal antibodies attenuates LSC self-renewal and reduces leukemia burden in AML patient-derived xenograft models but has negligible effect on normal hematopoietic stem/progenitor cells. Thus, our studies reveal the function of TMIGD2 in LSCs and provide a promising therapeutic strategy for AML.
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Affiliation(s)
- Hao Wang
- Department of Microbiology & Immunology, Albert Einstein College of Medicine, Bronx, NY, 10461, USA
| | - R Alejandro Sica
- Department of Medicine, Albert Einstein College of Medicine, Bronx, NY, 10461, USA
| | - Gurbakhash Kaur
- Department of Internal Medicine, UT Southwestern Medical Center, Dallas, TX, 75390, USA
| | - Phillip M Galbo
- Department of Microbiology & Immunology, Albert Einstein College of Medicine, Bronx, NY, 10461, USA
- Department of Genetics, Albert Einstein College of Medicine, Bronx, NY, 10461, USA
| | - Zhixin Jing
- Department of Pathology, Albert Einstein College of Medicine, Bronx, NY, 10461, USA
| | - Christopher D Nishimura
- Department of Microbiology & Immunology, Albert Einstein College of Medicine, Bronx, NY, 10461, USA
| | - Xiaoxin Ren
- Department of Microbiology & Immunology, Albert Einstein College of Medicine, Bronx, NY, 10461, USA
| | - Ankit Tanwar
- Department of Microbiology & Immunology, Albert Einstein College of Medicine, Bronx, NY, 10461, USA
| | | | - Britta Will
- Department of Medicine, Albert Einstein College of Medicine, Bronx, NY, 10461, USA
- Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY, 10461, USA
| | - Deyou Zheng
- Department of Genetics, Albert Einstein College of Medicine, Bronx, NY, 10461, USA
- Departments of Neurology and Neuroscience, Albert Einstein College of Medicine, Bronx, NY, 10461, USA
| | - David Fooksman
- Department of Pathology, Albert Einstein College of Medicine, Bronx, NY, 10461, USA
| | - Xingxing Zang
- Department of Microbiology & Immunology, Albert Einstein College of Medicine, Bronx, NY, 10461, USA.
- Department of Medicine, Albert Einstein College of Medicine, Bronx, NY, 10461, USA.
- Department of Urology, Albert Einstein College of Medicine, Bronx, NY, 10461, USA.
- Department of Oncology, Albert Einstein College of Medicine, Bronx, NY, 10461, USA.
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14
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Olejarz W, Basak G. Emerging Therapeutic Targets and Drug Resistance Mechanisms in Immunotherapy of Hematological Malignancies. Cancers (Basel) 2023; 15:5765. [PMID: 38136311 PMCID: PMC10741639 DOI: 10.3390/cancers15245765] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2023] [Revised: 11/22/2023] [Accepted: 12/06/2023] [Indexed: 12/24/2023] Open
Abstract
CAR-T cell therapy has revolutionized the treatment of hematological malignancies with high remission rates in the case of ALL and NHL. This therapy has some limitations such as long manufacturing periods, persistent restricted cell sources and high costs. Moreover, combination regimens increase the risk of immune-related adverse events, so the identification new therapeutic targets is important to minimize the risk of toxicities and to guide more effective approaches. Cancer cells employ several mechanisms to evade immunosurveillance, which causes resistance to immunotherapy; therefore, a very important therapeutic approach is to focus on the development of rational combinations of targeted therapies with non-overlapping toxicities. Recent progress in the development of new inhibitory clusters of differentiation (CDs), signaling pathway molecules, checkpoint inhibitors, and immunosuppressive cell subsets and factors in the tumor microenvironment (TME) has significantly improved anticancer responses. Novel strategies regarding combination immunotherapies with CAR-T cells are the most promising approach to cure cancer.
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Affiliation(s)
- Wioletta Olejarz
- Department of Biochemistry and Pharmacogenomics, Faculty of Pharmacy, Medical University of Warsaw, 02-091 Warsaw, Poland
- Centre for Preclinical Research, Medical University of Warsaw, 02-091 Warsaw, Poland
| | - Grzegorz Basak
- Department of Hematology, Transplantation and Internal Medicine, Medical University of Warsaw, 02-091 Warsaw, Poland;
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15
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Zenebe B, Nigussie H, Belay G, Seboka N. A review on characterization of BCR - ABL transcript variants for molecular monitoring of chronic myeloid leukemia phenotypes. Hematology 2023; 28:2284038. [PMID: 37982440 DOI: 10.1080/16078454.2023.2284038] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2023] [Accepted: 11/02/2023] [Indexed: 11/21/2023] Open
Abstract
Chronic myeloid leukemia (CML) is a clonal myeloproliferative growth of human pluripotent stem cells which is estimated to occur at a rate of 1/100000 populations every year worldwide. A characteristic feature of this disease is the presence of the Philadelphia chromosome genotype, which results from the reciprocal translocation between human chromosomes 9 and 22. Two types of major genotypes are involved, which consequently result in two major types of expressed fusion mRNA transcripts: b3a2 and b2a2, i.e. major breakpoint segments (happening after exon 13 & after exon 14) of the BCR gene on chromosome 22 fuze with the ABL1 gene breakpoint (happening after exon 2) on chromosome 9, forming two genotypes coding for two transcripts: b3a2 (e14a2) and b2a2 (e13a2). The protein 'p210 BCR-ABL1', a protein which characteristically exhibits a high tyrosine kinase activity which is followed by the activation of various cellular processes that lead to increased cellular proliferation and cancer, is coded by both major BCR - ABL1 mRNA transcripts. Recent developments in the treatment of CML through molecular monitoring of the disease have managed to reduce patient morbidity and mortality. Advanced molecular techniques are aimed at detecting BCR-ABL1 transcript levels to monitor treatment response. Transcript typing is necessary to detect minimal residual disease and to achieve molecular response by helping to provide selective therapy based on the type of transcript identified, as transcript type is correlated with the disease course.The purpose of this review is to discuss: the role of the BCR-ABL1 fusion gene in the pathogenesis of CML; the role of BCR-ABL1 transcript characterization in the molecular monitoring of CML therapy; the association of BCR - ABL1 transcript types with different CML phenotypes, molecular responses, and treatment responses; and the laboratory techniques employed to detect and characterize BCR - ABL1 transcripts.
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Affiliation(s)
- Benyam Zenebe
- Microbial Cellular and Molecular Biology Department, Addis Ababa University, Addis Ababa, Ethiopia
| | - Helen Nigussie
- Microbial Cellular and Molecular Biology Department, Addis Ababa University, Addis Ababa, Ethiopia
| | - Gurja Belay
- Microbial Cellular and Molecular Biology Department, Addis Ababa University, Addis Ababa, Ethiopia
| | - Nigussie Seboka
- Microbial Cellular and Molecular Biology Department, Addis Ababa University, Addis Ababa, Ethiopia
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16
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Xie J, Mo T, Li R, Zhang H, Liang G, Ma T, Chen J, Xie H, Wen X, Hu T, Xian Z, Pan W. The m 7G Reader NCBP2 Promotes Pancreatic Cancer Progression by Upregulating MAPK/ERK Signaling. Cancers (Basel) 2023; 15:5454. [PMID: 38001714 PMCID: PMC10670634 DOI: 10.3390/cancers15225454] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2023] [Revised: 11/02/2023] [Accepted: 11/03/2023] [Indexed: 11/26/2023] Open
Abstract
PDAC is one of the most common malignant tumors worldwide. The difficulty of early diagnosis and lack of effective treatment are the main reasons for its poor prognosis. Therefore, it is urgent to identify novel diagnostic and therapeutic targets for PDAC patients. The m7G methylation is a common type of RNA modification that plays a pivotal role in regulating tumor development. However, the correlation between m7G regulatory genes and PDAC progression remains unclear. By integrating gene expression and related clinical information of PDAC patients from TCGA and GEO cohorts, m7G binding protein NCBP2 was found to be highly expressed in PDAC patients. More importantly, PDAC patients with high NCBP2 expression had a worse prognosis. Stable NCBP2-knockdown and overexpression PDAC cell lines were constructed to further perform in-vitro and in-vivo experiments. NCBP2-knockdown significantly inhibited PDAC cell proliferation, while overexpression of NCBP2 dramatically promoted PDAC cell growth. Mechanistically, NCBP2 enhanced the translation of c-JUN, which in turn activated MEK/ERK signaling to promote PDAC progression. In conclusion, our study reveals that m7G reader NCBP2 promotes PDAC progression by activating MEK/ERK pathway, which could serve as a novel therapeutic target for PDAC patients.
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Affiliation(s)
- Jiancong Xie
- Department of General Surgery (Pancreatic Hepatobiliary Surgery), The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou 510655, China; (J.X.); (H.Z.); (T.M.)
| | - Taiwei Mo
- Department of General Surgery, The First Affiliated Hospital of Jinan University, Guangzhou 510630, China;
- Department of General Surgery (Colorectal Surgery), The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou 510655, China; (R.L.); (G.L.); (J.C.); (H.X.); (X.W.); (T.H.)
| | - Ruibing Li
- Department of General Surgery (Colorectal Surgery), The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou 510655, China; (R.L.); (G.L.); (J.C.); (H.X.); (X.W.); (T.H.)
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, Guangdong Institute of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou 510655, China
- Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou 510655, China
| | - Hao Zhang
- Department of General Surgery (Pancreatic Hepatobiliary Surgery), The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou 510655, China; (J.X.); (H.Z.); (T.M.)
| | - Guanzhan Liang
- Department of General Surgery (Colorectal Surgery), The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou 510655, China; (R.L.); (G.L.); (J.C.); (H.X.); (X.W.); (T.H.)
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, Guangdong Institute of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou 510655, China
- Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou 510655, China
| | - Tao Ma
- Department of General Surgery (Pancreatic Hepatobiliary Surgery), The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou 510655, China; (J.X.); (H.Z.); (T.M.)
| | - Jing Chen
- Department of General Surgery (Colorectal Surgery), The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou 510655, China; (R.L.); (G.L.); (J.C.); (H.X.); (X.W.); (T.H.)
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, Guangdong Institute of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou 510655, China
- Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou 510655, China
| | - Hanlin Xie
- Department of General Surgery (Colorectal Surgery), The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou 510655, China; (R.L.); (G.L.); (J.C.); (H.X.); (X.W.); (T.H.)
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, Guangdong Institute of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou 510655, China
- Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou 510655, China
| | - Xiaofeng Wen
- Department of General Surgery (Colorectal Surgery), The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou 510655, China; (R.L.); (G.L.); (J.C.); (H.X.); (X.W.); (T.H.)
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, Guangdong Institute of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou 510655, China
- Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou 510655, China
| | - Tuo Hu
- Department of General Surgery (Colorectal Surgery), The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou 510655, China; (R.L.); (G.L.); (J.C.); (H.X.); (X.W.); (T.H.)
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, Guangdong Institute of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou 510655, China
- Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou 510655, China
| | - Zhenyu Xian
- Department of General Surgery (Colorectal Surgery), The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou 510655, China; (R.L.); (G.L.); (J.C.); (H.X.); (X.W.); (T.H.)
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, Guangdong Institute of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou 510655, China
- Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou 510655, China
| | - Weidong Pan
- Department of General Surgery (Pancreatic Hepatobiliary Surgery), The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou 510655, China; (J.X.); (H.Z.); (T.M.)
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Jamal M, Lei Y, He H, Zeng X, Bangash HI, Xiao D, Shao L, Zhou F, Zhang Q. CCR9 overexpression promotes T-ALL progression by enhancing cholesterol biosynthesis. Front Pharmacol 2023; 14:1257289. [PMID: 37745085 PMCID: PMC10512069 DOI: 10.3389/fphar.2023.1257289] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2023] [Accepted: 08/22/2023] [Indexed: 09/26/2023] Open
Abstract
Introduction: T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy of the lymphoid progenitor cells, contributing to ∼ 20% of the total ALL cases, with a higher prevalence in adults than children. Despite the important role of human T-ALL cell lines in understanding the pathobiology of the disease, a detailed comparison of the tumorigenic potentials of two commonly used T-ALL cell lines, MOLT4 and JURKAT cells, is still lacking. Methodology: In the present study, NOD-Prkdc scid IL2rgd ull (NTG) mice were intravenously injected with MOLT4, JURKAT cells, and PBS as a control. The leukemiac cell homing/infiltration into the bone marrow, blood, liver and spleen was investigated for bioluminescence imaging, flow cytometry, and immunohistochemistry staining. Gene expression profiling of the two cell lines was performed via RNA-seq to identify the differentially expressed genes (DEGs). CCR9 identified as a DEG, was further screened for its role in invasion and metastasis in both cell lines in vitro. Moreover, a JURKAT cell line with overexpressed CCR9 (Jurkat-OeCCR9) was investigated for T-ALL formation in the NTG mice as compared to the GFP control. Jurkat-OeCCR9 cells were then subjected to transcriptome analysis to identify the genes and pathways associated with the upregulation of CCR9 leading to enhanced tumirogenesis. The DEGs of the CCR9-associated upregulation were validated both at mRNA and protein levels. Simvastatin was used to assess the effect of cholesterol biosynthesis inhibition on the aggressiveness of T-ALL cells. Results: Comparison of the leukemogenic potentials of the two T-ALL cell lines showed the relatively higher leukemogenic potential of MOLT4 cells, characterized by their enhanced tissue infiltration in NOD-PrkdcscidIL2rgdull (NTG) mice. Transcriptmoe analysis of the two cell lines revealed numerous DEGs, including CCR9, enriched in vital signaling pathways associated with growth and proliferation. Notably, the upregulation of CCR9 also promoted the tissue infiltration of JURKAT cells in vitro and in NTG mice. Transcriptome analysis revealed that CCR9 overexpression facilitated cholesterol production by upregulating the expression of the transcriptional factor SREBF2, and the downstream genes: MSMO1, MVD, HMGCS1, and HMGCR, which was then corroborated at the protein levels. Notably, simvastatin treatment reduced the migration of the CCR9-overexpressing JURKAT cells, suggesting the importance of cholesterol in T-ALL progression. Conclusions: This study highlights the distinct tumorigenic potentials of two T-ALL cell lines and reveals CCR9-regulated enhanced cholesterol biosynthesis in T-ALL.
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Affiliation(s)
- Muhammad Jamal
- Department of Immunology, School of Basic Medical Sciences, Wuhan University, Wuhan, China
| | - Yufei Lei
- Department of Immunology, School of Basic Medical Sciences, Wuhan University, Wuhan, China
| | - Hengjing He
- Department of Immunology, School of Basic Medical Sciences, Wuhan University, Wuhan, China
| | - Xingruo Zeng
- Department of Immunology, School of Basic Medical Sciences, Wuhan University, Wuhan, China
| | - Hina Iqbal Bangash
- State Key Laboratory of Agricultural Microbiology, Hubei Hongshan Laboratory, College of Life Science and Technology, Huazhong Agricultural University, Wuhan, Hubei, China
| | - Di Xiao
- Department of Immunology, School of Basic Medical Sciences, Wuhan University, Wuhan, China
| | - Liang Shao
- Department of Hematology, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Fuling Zhou
- Department of Hematology, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Quiping Zhang
- Department of Immunology, School of Basic Medical Sciences, Wuhan University, Wuhan, China
- Hubei Provincial Key Laboratory of Developmentally Originated Disease, Wuhan University, Wuhan, China
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18
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Wilhelm T, Toledo MAS, Simons I, Stuth C, Mohta V, Mülfarth R, Nitsche M, Maschke-Neuß K, Schmitz S, Kaiser A, Panse J, Christen D, Arock M, Zenke M, Huber M. Capitalizing on paradoxical activation of the mitogen-activated protein kinase pathway for treatment of Imatinib-resistant mast cell leukemia. Hematol Oncol 2023; 41:520-534. [PMID: 36383121 DOI: 10.1002/hon.3100] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2021] [Revised: 08/29/2022] [Accepted: 11/14/2022] [Indexed: 11/17/2022]
Abstract
Prevention of fatal side effects during cancer therapy of cancer patients with high-dosed pharmacological inhibitors is to date a major challenge. Moreover, the development of drug resistance poses severe problems for the treatment of patients with leukemia or solid tumors. Particularly drug-mediated dimerization of RAF kinases can be the cause of acquired resistance, also called "paradoxical activation." In the present work we re-analyzed the effects of different tyrosine kinase inhibitors (TKIs) on the proliferation, metabolic activity, and survival of the Imatinib-resistant, KIT V560G, D816V-expressing human mast cell (MC) leukemia (MCL) cell line HMC-1.2. We observed that low concentrations of the TKIs Nilotinib and Ponatinib resulted in enhanced proliferation, suggesting paradoxical activation of the MAPK pathway. Indeed, these TKIs caused BRAF-CRAF dimerization, resulting in ERK1/2 activation. The combination of Ponatinib with the MEK inhibitor Trametinib, at nanomolar concentrations, effectively suppressed HMC-1.2 proliferation, metabolic activity, and induced apoptotic cell death. Effectiveness of this drug combination was recapitulated in the human KIT D816V MC line ROSAKIT D816V and in KIT D816V hematopoietic progenitors obtained from patient-derived induced pluripotent stem cells (iPS cells) and systemic mastocytosis patient samples. In conclusion, mutated KIT-driven Imatinib resistance and possible TKI-induced paradoxical activation can be efficiently overcome by a low concentration Ponatinib and Trametinib co-treatment, potentially reducing the negative side effects associated with MCL therapy.
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Affiliation(s)
- Thomas Wilhelm
- Institute of Biochemistry and Molecular Immunology, Medical Faculty, RWTH Aachen University, Aachen, Germany
| | - Marcelo A S Toledo
- Department of Cell Biology, Institute for Biomedical Engineering, RWTH Aachen University Medical School, Aachen, Germany
- Helmholtz-Institute for Biomedical Engineering, RWTH Aachen University, Aachen, Germany
- Department of Hematology, Oncology, Hemostaseology and Stem Cell Transplantation, Faculty of Medicine, RWTH Aachen University Medical School, Aachen, Germany
- Center for Integrated Oncology Aachen Bonn Cologne Düsseldorf (CIO ABCD), Aachen, Germany
| | - Ilka Simons
- Institute of Biochemistry and Molecular Immunology, Medical Faculty, RWTH Aachen University, Aachen, Germany
| | - Christian Stuth
- Institute of Biochemistry and Molecular Immunology, Medical Faculty, RWTH Aachen University, Aachen, Germany
| | - Vrinda Mohta
- Institute of Biochemistry and Molecular Immunology, Medical Faculty, RWTH Aachen University, Aachen, Germany
| | - Ronja Mülfarth
- Institute of Biochemistry and Molecular Immunology, Medical Faculty, RWTH Aachen University, Aachen, Germany
| | - Marcus Nitsche
- Institute of Biochemistry and Molecular Immunology, Medical Faculty, RWTH Aachen University, Aachen, Germany
| | - Karin Maschke-Neuß
- Institute of Biochemistry and Molecular Immunology, Medical Faculty, RWTH Aachen University, Aachen, Germany
| | - Susanne Schmitz
- Department of Cell Biology, Institute for Biomedical Engineering, RWTH Aachen University Medical School, Aachen, Germany
- Helmholtz-Institute for Biomedical Engineering, RWTH Aachen University, Aachen, Germany
| | - Anne Kaiser
- Department of Hematology, Oncology, Hemostaseology and Stem Cell Transplantation, Faculty of Medicine, RWTH Aachen University Medical School, Aachen, Germany
- Center for Integrated Oncology Aachen Bonn Cologne Düsseldorf (CIO ABCD), Aachen, Germany
| | - Jens Panse
- Department of Hematology, Oncology, Hemostaseology and Stem Cell Transplantation, Faculty of Medicine, RWTH Aachen University Medical School, Aachen, Germany
- Center for Integrated Oncology Aachen Bonn Cologne Düsseldorf (CIO ABCD), Aachen, Germany
| | - Deborah Christen
- Department of Hematology, Oncology, Hemostaseology and Stem Cell Transplantation, Faculty of Medicine, RWTH Aachen University Medical School, Aachen, Germany
- Center for Integrated Oncology Aachen Bonn Cologne Düsseldorf (CIO ABCD), Aachen, Germany
| | - Michel Arock
- Department of Hematological Biology, Pitié-Salpêtrière Hospital, Pierre et Marie Curie University (UPMC), Paris, France
| | - Martin Zenke
- Department of Cell Biology, Institute for Biomedical Engineering, RWTH Aachen University Medical School, Aachen, Germany
- Helmholtz-Institute for Biomedical Engineering, RWTH Aachen University, Aachen, Germany
- Department of Hematology, Oncology, Hemostaseology and Stem Cell Transplantation, Faculty of Medicine, RWTH Aachen University Medical School, Aachen, Germany
- Center for Integrated Oncology Aachen Bonn Cologne Düsseldorf (CIO ABCD), Aachen, Germany
| | - Michael Huber
- Institute of Biochemistry and Molecular Immunology, Medical Faculty, RWTH Aachen University, Aachen, Germany
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19
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Langhammer M, Schöpf J, Jaquet T, Horn K, Angel M, Spohr C, Christen D, Uhl FM, Maié T, Jacobi H, Feyerabend TB, Huber J, Panning M, Sitaru C, Costa I, Zeiser R, Aumann K, Becker H, Braunschweig T, Koschmieder S, Shoumariyeh K, Huber M, Schemionek-Reinders M, Brummer T, Halbach S. Mast cell deficiency prevents BCR::ABL1 induced splenomegaly and cytokine elevation in a CML mouse model. Leukemia 2023; 37:1474-1484. [PMID: 37161070 PMCID: PMC10317838 DOI: 10.1038/s41375-023-01916-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2022] [Revised: 04/19/2023] [Accepted: 04/21/2023] [Indexed: 05/11/2023]
Abstract
The persistence of leukemic stem cells (LSCs) represents a problem in the therapy of chronic myeloid leukemia (CML). Hence, it is of utmost importance to explore the underlying mechanisms to develop new therapeutic approaches to cure CML. Using the genetically engineered ScltTA/TRE-BCR::ABL1 mouse model for chronic phase CML, we previously demonstrated that the loss of the docking protein GAB2 counteracts the infiltration of mast cells (MCs) in the bone marrow (BM) of BCR::ABL1 positive mice. Here, we show for the first time that BCR::ABL1 drives the cytokine independent expansion of BM derived MCs and sensitizes them for FcεRI triggered degranulation. Importantly, we demonstrate that genetic mast cell deficiency conferred by the Cpa3Cre allele prevents BCR::ABL1 induced splenomegaly and impairs the production of pro-inflammatory cytokines. Furthermore, we show in CML patients that splenomegaly is associated with high BM MC counts and that upregulation of pro-inflammatory cytokines in patient serum samples correlates with tryptase levels. Finally, MC-associated transcripts were elevated in human CML BM samples. Thus, our study identifies MCs as essential contributors to disease progression and suggests considering them as an additional target in CML therapy. Mast cells play a key role in the pro-inflammatory tumor microenvironment of the bone marrow. Shown is a cartoon summarizing our results from the mouse model. BCR::ABL1 transformed MCs, as part of the malignant clone, are essential for the elevation of pro-inflammatory cytokines, known to be important in disease initiation and progression.
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Affiliation(s)
- Melanie Langhammer
- Institute of Molecular Medicine, ZBMZ, Faculty of Medicine, University of Freiburg, Freiburg, Germany
- Faculty of Biology, University of Freiburg, Freiburg, Germany
| | - Julia Schöpf
- Institute of Molecular Medicine, ZBMZ, Faculty of Medicine, University of Freiburg, Freiburg, Germany
- Faculty of Biology, University of Freiburg, Freiburg, Germany
| | - Timo Jaquet
- Department of Hematology, Oncology, Hemostaseology, and Stem Cell Transplantation, Faculty of Medicine, RWTH Aachen University, Aachen, Germany
- Center for Integrated Oncology Aachen Bonn Cologne Düsseldorf (CIO ABCD), Aachen, Germany
| | - Katharina Horn
- Institute of Biochemistry and Molecular Immunology, RWTH Aachen University, Aachen, Germany
| | - Moritz Angel
- Institute of Molecular Medicine, ZBMZ, Faculty of Medicine, University of Freiburg, Freiburg, Germany
- Faculty of Biology, University of Freiburg, Freiburg, Germany
| | - Corinna Spohr
- Institute of Molecular Medicine, ZBMZ, Faculty of Medicine, University of Freiburg, Freiburg, Germany
- Faculty of Biology, University of Freiburg, Freiburg, Germany
- Spemann Graduate School of Biology and Medicine, University of Freiburg, Freiburg, Germany
| | - Daniel Christen
- Institute of Molecular Medicine, ZBMZ, Faculty of Medicine, University of Freiburg, Freiburg, Germany
- Faculty of Biology, University of Freiburg, Freiburg, Germany
| | - Franziska Maria Uhl
- Faculty of Biology, University of Freiburg, Freiburg, Germany
- Department of Medicine I, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Tiago Maié
- Institute for Computational Genomics, University Hospital, RWTH Aachen University, Aachen, Germany
| | - Henrike Jacobi
- Department of Hematology, Oncology, Hemostaseology, and Stem Cell Transplantation, Faculty of Medicine, RWTH Aachen University, Aachen, Germany
- Center for Integrated Oncology Aachen Bonn Cologne Düsseldorf (CIO ABCD), Aachen, Germany
| | - Thorsten B Feyerabend
- Division of Cellular Immunology, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Julia Huber
- Department of Pathology, Institute for Surgical Pathology, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Marcus Panning
- Institute of Virology, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Cassian Sitaru
- Department of Dermatology, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Ivan Costa
- Institute for Computational Genomics, University Hospital, RWTH Aachen University, Aachen, Germany
| | - Robert Zeiser
- Department of Medicine I, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany
- German Cancer Consortium (DKTK), Partner Site Freiburg and German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Konrad Aumann
- Department of Pathology, Institute for Surgical Pathology, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Heiko Becker
- Department of Medicine I, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany
- German Cancer Consortium (DKTK), Partner Site Freiburg and German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Till Braunschweig
- Department of Pathology, University Hospital, RWTH Aachen University, Aachen, Germany
| | - Steffen Koschmieder
- Department of Hematology, Oncology, Hemostaseology, and Stem Cell Transplantation, Faculty of Medicine, RWTH Aachen University, Aachen, Germany
- Center for Integrated Oncology Aachen Bonn Cologne Düsseldorf (CIO ABCD), Aachen, Germany
| | - Khalid Shoumariyeh
- Department of Medicine I, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany
- German Cancer Consortium (DKTK), Partner Site Freiburg and German Cancer Research Center (DKFZ), Heidelberg, Germany
- Comprehensive Cancer Center Freiburg (CCCF), Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Michael Huber
- Institute of Biochemistry and Molecular Immunology, RWTH Aachen University, Aachen, Germany
| | - Mirle Schemionek-Reinders
- Department of Hematology, Oncology, Hemostaseology, and Stem Cell Transplantation, Faculty of Medicine, RWTH Aachen University, Aachen, Germany
- Center for Integrated Oncology Aachen Bonn Cologne Düsseldorf (CIO ABCD), Aachen, Germany
| | - Tilman Brummer
- Institute of Molecular Medicine, ZBMZ, Faculty of Medicine, University of Freiburg, Freiburg, Germany
- German Cancer Consortium (DKTK), Partner Site Freiburg and German Cancer Research Center (DKFZ), Heidelberg, Germany
- Comprehensive Cancer Center Freiburg (CCCF), Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany
- Center for Biological Signalling Studies BIOSS, University of Freiburg, Freiburg, Germany
| | - Sebastian Halbach
- Institute of Molecular Medicine, ZBMZ, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
- German Cancer Consortium (DKTK), Partner Site Freiburg and German Cancer Research Center (DKFZ), Heidelberg, Germany.
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20
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Nigam M, Mishra AP, Deb VK, Dimri DB, Tiwari V, Bungau SG, Bungau AF, Radu AF. Evaluation of the association of chronic inflammation and cancer: Insights and implications. Biomed Pharmacother 2023; 164:115015. [PMID: 37321055 DOI: 10.1016/j.biopha.2023.115015] [Citation(s) in RCA: 45] [Impact Index Per Article: 22.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2023] [Revised: 06/02/2023] [Accepted: 06/11/2023] [Indexed: 06/17/2023] Open
Abstract
Among the most extensively researched processes in the development and treatment of cancer is inflammatory condition. Although acute inflammation is essential for the wound healing and reconstruction of tissues that have been damaged, chronic inflammation may contribute to the onset and growth of a number of diseases, including cancer. By disrupting the signaling processes of cells, which result in cancer induction, invasion, and development, a variety of inflammatory molecules are linked to the development of cancer. The microenvironment surrounding the tumor is greatly influenced by inflammatory cells and their subsequent secretions, which also contribute significantly to the tumor's growth, survivability, and potential migration. These inflammatory variables have been mentioned in several publications as prospective diagnostic tools for anticipating the onset of cancer. Targeting inflammation with various therapies can reduce the inflammatory response and potentially limit or block the proliferation of cancer cells. The scientific medical literature from the past three decades has been studied to determine how inflammatory chemicals and cell signaling pathways related to cancer invasion and metastasis are related. The current narrative review updates the relevant literature while highlighting the specifics of inflammatory signaling pathways in cancer and their possible therapeutic possibilities.
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Affiliation(s)
- Manisha Nigam
- Department of Biochemistry, Hemvati Nandan Bahuguna Garhwal University, 246174 Srinagar Garhwal, Uttarakhand, India
| | - Abhay Prakash Mishra
- Department of Pharmacology, Faculty of Health Science, University of Free State, 9300 Bloemfontein, South Africa.
| | - Vishal Kumar Deb
- Dietetics and Nutrition Technology Division, CSIR Institute of Himalayan Bioresource Technology, 176061 Palampur, Himanchal Pradesh, India
| | - Deen Bandhu Dimri
- Department of Biochemistry, Hemvati Nandan Bahuguna Garhwal University, 246174 Srinagar Garhwal, Uttarakhand, India
| | - Vinod Tiwari
- Department of Pharmaceutical Engineering & Technology, Indian Institute of Technology BHU, Varanasi 221005, Uttar Pradesh, India
| | - Simona Gabriela Bungau
- Doctoral School of Biomedical Sciences, University of Oradea, 410087 Oradea, Romania; Department of Pharmacy, Faculty of Medicine and Pharmacy, University of Oradea, 410028 Oradea, Romania.
| | - Alexa Florina Bungau
- Doctoral School of Biomedical Sciences, University of Oradea, 410087 Oradea, Romania
| | - Andrei-Flavius Radu
- Doctoral School of Biomedical Sciences, University of Oradea, 410087 Oradea, Romania; Department of Preclinical Disciplines, Faculty of Medicine and Pharmacy, University of Oradea, 410073 Oradea, Romania
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21
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Gurkan-Alp AS, Karabay AZ, Koc A, Buyukbingol E. Novel indole retinoid derivative induces apoptosis and cell cycle arrest and modulates AKT and ERK signaling in HL-60 cells. Fundam Clin Pharmacol 2023; 37:557-565. [PMID: 36690337 DOI: 10.1111/fcp.12876] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2022] [Revised: 01/09/2023] [Accepted: 01/20/2023] [Indexed: 01/25/2023]
Abstract
Chemotherapy with targeted drugs is the first line therapy option for acute and chronic myeloid leukemia. However, hematopoietic stem cell transplantation may be used in high-risk patients or patients with failed responses to chemo drugs. Discovery and development of more effective new agents with lower side effects is the main aim of leukemia treatment. In this study, a novel retinoid compound with tetrahydronaphthalene ring was synthesized and evaluated for anticancer activity in human chronic and acute myeloid leukemia cell lines K562 and HL-60. Novel N-(1H-indol-1-yl)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene-2-carboxamide was synthesized based on molecular hybridization of the two different bioactive structures retinoid head and indole. The effects of the synthesized carboxamide compound, which was referred to as compound 5, were determined in K562 chronic myeloid leukemia and HL-60 acute myeloid leukemia cell lines and L929 fibroblast cell line, which served as a control. Colorimetric MTT and caspase3 activity tests, flow cytometry, western blot, and microscopic examinations were used to evaluate biological activity. Compound 5 more effectively induced cell death in HL60 cells in comparison to K562 cells and L929 fibroblast cells. Therefore, further mechanism of cell death was investigated in HL60 cell line. It was found that compound 5 induced remarkable cytotoxicity, caspase3 activation, and PARP fragmentation in HL60 cells. Flow cytometric staining showed that the percentage of cells arrested in G0/G1 was also increased with compound 5 treatment. Important modulator proteins of cell proliferation p-ERK, p-AKT, and p-m-TOR were also found to be inhibited with compound 5 treatment. Collectively, our results reveal compound 5, which is a novel indole retinoid compound as a potential active agent for the treatment of acute promyelocytic leukemia.
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Affiliation(s)
- A Selen Gurkan-Alp
- Faculty of Pharmacy, Department of Pharmaceutical Chemistry, Ankara University, Ankara, Turkey
| | - Arzu Z Karabay
- Faculty of Pharmacy, Department of Biochemistry, Ankara University, Ankara, Turkey
| | - Asli Koc
- Faculty of Pharmacy, Department of Biochemistry, Ankara University, Ankara, Turkey
| | - Erdem Buyukbingol
- Faculty of Pharmacy, Department of Pharmaceutical Chemistry, Ankara University, Ankara, Turkey
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22
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Miyasato S, Iwata K, Mura R, Nakamura S, Yanagida K, Shindou H, Nagata Y, Kawahara M, Yamaguchi S, Aoki J, Inoue A, Nagamune T, Shimizu T, Nakamura M. Constitutively active GPR43 is crucial for proper leukocyte differentiation. FASEB J 2023; 37:e22676. [PMID: 36468834 DOI: 10.1096/fj.202201591r] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2022] [Revised: 11/13/2022] [Accepted: 11/17/2022] [Indexed: 12/12/2022]
Abstract
The G protein-coupled receptors, GPR43 (free fatty acid receptor 2, FFA2) and GPR41 (free fatty acid receptor 3, FFA3), are activated by short-chain fatty acids produced under various conditions, including microbial fermentation of carbohydrates. Previous studies have implicated this receptor energy homeostasis and immune responses as well as in cell growth arrest and apoptosis. Here, we observed the expression of both receptors in human blood cells and a remarkable enhancement in leukemia cell lines (HL-60, U937, and THP-1 cells) during differentiation. A reporter assay revealed that GPR43 is coupled with Gαi and Gα12/13 and is constitutively active without any stimuli. Specific blockers of GPR43, GLPG0974 and CATPB function as inverse agonists because treatment with these compounds significantly reduces constitutive activity. In HL-60 cells, enhanced expression of GPR43 led to growth arrest through Gα12/13 . In addition, the blockage of GPR43 activity in these cells significantly impaired their adherent properties due to the reduction of adhesion molecules. We further revealed that enhanced GPR43 activity induces F-actin formation. However, the activity of GPR43 did not contribute to butyrate-induced apoptosis in differentiated HL-60 cells because of the ineffectiveness of the inverse agonist on cell death. Collectively, these results suggest that GPR43, which possesses constitutive activity, is crucial for growth arrest, followed by the proper differentiation of leukocytes.
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Affiliation(s)
- Sosuke Miyasato
- Department of Bioscience, Graduate School of Life Science, Okayama University of Science, Okayama, Japan
| | - Kurumi Iwata
- Department of Bioscience, Graduate School of Life Science, Okayama University of Science, Okayama, Japan
| | - Reika Mura
- Department of Bioscience, Graduate School of Life Science, Okayama University of Science, Okayama, Japan
| | - Shou Nakamura
- Department of Chemistry and Biotechnology, Graduate School of Engineering, The University of Tokyo, Tokyo, Japan
| | - Keisuke Yanagida
- Department of Lipid Life Science, National Center for Global Health and Medicine, Tokyo, Japan
| | - Hideo Shindou
- Department of Lipid Life Science, National Center for Global Health and Medicine, Tokyo, Japan.,Department of Medical Lipid Science, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Yosuke Nagata
- Department of Bioscience, Graduate School of Life Science, Okayama University of Science, Okayama, Japan
| | - Masahiro Kawahara
- Department of Chemistry and Biotechnology, Graduate School of Engineering, The University of Tokyo, Tokyo, Japan.,Laboratory of Cell Vaccine, Center for Vaccine and Adjuvant Research (CVAR), National Institutes of Biomedical Innovation, Health and Nutrition (NIBIOHN), Osaka, Japan
| | - Satoshi Yamaguchi
- Department of Chemistry and Biotechnology, Graduate School of Engineering, The University of Tokyo, Tokyo, Japan
| | - Junken Aoki
- Department of Health Chemistry, Graduate School of Pharmaceutical Science, The University of Tokyo, Tokyo, Japan.,Japan Agency for Medical Research and Development (AMED), Core Research for Evolutional Science and Technology (AMED-CREST), Tokyo, Japan
| | - Asuka Inoue
- Department of Molecular and Cellular Biochemistry, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan
| | - Teruyuki Nagamune
- Department of Chemistry and Biotechnology, Graduate School of Engineering, The University of Tokyo, Tokyo, Japan
| | - Takao Shimizu
- Lipid Signaling, National Center for Global Health and Medicine, Tokyo, Japan.,Institute of Microbial Chemistry, Tokyo, Japan
| | - Motonao Nakamura
- Department of Bioscience, Graduate School of Life Science, Okayama University of Science, Okayama, Japan
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23
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Sharma M, Anandram S, Ross C, Srivastava S. FUBP3 regulates chronic myeloid leukaemia progression through PRC2 complex regulated PAK1-ERK signalling. J Cell Mol Med 2022; 27:15-29. [PMID: 36478132 PMCID: PMC9806296 DOI: 10.1111/jcmm.17584] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2022] [Revised: 09/08/2022] [Accepted: 09/17/2022] [Indexed: 12/13/2022] Open
Abstract
The development of resistance and heterogeneity in differential response towards tyrosine kinase inhibitors (TKI) in chronic myeloid leukaemia (CML) treatment has led to the exploration of factors independent of the Philadelphia chromosome. Among these are the association of deletions of genes on derivative (der) 9 chromosome with adverse outcomes in CML patients. However, the functional role of genes near the breakpoint on der (9) in CML prognosis and progression remains largely unexplored. Copy number variation and mRNA expression were evaluated for five genes located near the breakpoint on der (9). Our data showed a significant association between microdeletions of the FUBP3 gene and its reduced expression with poor prognostic markers and adverse response outcomes in CML patients. Further investigation using K562 cells showed that the decrease in FUBP3 protein was associated with an increase in proliferation and survival due to activation of the MAPK-ERK pathway. We have established a novel direct interaction of FUBP3 protein and PRC2 complex in the regulation of ERK signalling via PAK1. Our findings demonstrate the role of the FUBP3 gene located on der (9) in poor response and progression in CML with the identification of additional druggable targets such as PAK1 in improving response outcomes in CML patients.
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Affiliation(s)
- Mugdha Sharma
- Department of MedicineSt. John's Medical College and HospitalBengaluruIndia
- St. John's National Academy of Health SciencesBengaluruIndia
| | - Seetharam Anandram
- St. John's National Academy of Health SciencesBengaluruIndia
- Department of Clinical HematologySt. John's Medical College and HospitalBengaluruIndia
| | - Cecil Ross
- St. John's National Academy of Health SciencesBengaluruIndia
- Department of Clinical HematologySt. John's Medical College and HospitalBengaluruIndia
| | - Sweta Srivastava
- St. John's National Academy of Health SciencesBengaluruIndia
- Department of Transfusion Medicine and ImmunohematologySt. John's Medical College and HospitalBengaluruIndia
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24
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Carigga Gutierrez NM, Pujol-Solé N, Arifi Q, Coll JL, le Clainche T, Broekgaarden M. Increasing cancer permeability by photodynamic priming: from microenvironment to mechanotransduction signaling. Cancer Metastasis Rev 2022; 41:899-934. [PMID: 36155874 DOI: 10.1007/s10555-022-10064-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/01/2022] [Accepted: 09/06/2022] [Indexed: 01/25/2023]
Abstract
The dense cancer microenvironment is a significant barrier that limits the penetration of anticancer agents, thereby restraining the efficacy of molecular and nanoscale cancer therapeutics. Developing new strategies to enhance the permeability of cancer tissues is of major interest to overcome treatment resistance. Nonetheless, early strategies based on small molecule inhibitors or matrix-degrading enzymes have led to disappointing clinical outcomes by causing increased chemotherapy toxicity and promoting disease progression. In recent years, photodynamic therapy (PDT) has emerged as a novel approach to increase the permeability of cancer tissues. By producing excessive amounts of reactive oxygen species selectively in the cancer microenvironment, PDT increases the accumulation, penetration depth, and efficacy of chemotherapeutics. Importantly, the increased cancer permeability has not been associated to increased metastasis formation. In this review, we provide novel insights into the mechanisms by which this effect, called photodynamic priming, can increase cancer permeability without promoting cell migration and dissemination. This review demonstrates that PDT oxidizes and degrades extracellular matrix proteins, reduces the capacity of cancer cells to adhere to the altered matrix, and interferes with mechanotransduction pathways that promote cancer cell migration and differentiation. Significant knowledge gaps are identified regarding the involvement of critical signaling pathways, and to which extent these events are influenced by the complicated PDT dosimetry. Addressing these knowledge gaps will be vital to further develop PDT as an adjuvant approach to improve cancer permeability, demonstrate the safety and efficacy of this priming approach, and render more cancer patients eligible to receive life-extending treatments.
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Affiliation(s)
| | - Núria Pujol-Solé
- Université Grenoble Alpes, Inserm U 1209, CNRS UMR 5309, Institute for Advanced Biosciences, 38000, Grenoble, France
| | - Qendresa Arifi
- Université Grenoble Alpes, Inserm U 1209, CNRS UMR 5309, Institute for Advanced Biosciences, 38000, Grenoble, France
| | - Jean-Luc Coll
- Université Grenoble Alpes, Inserm U 1209, CNRS UMR 5309, Institute for Advanced Biosciences, 38000, Grenoble, France
| | - Tristan le Clainche
- Université Grenoble Alpes, Inserm U 1209, CNRS UMR 5309, Institute for Advanced Biosciences, 38000, Grenoble, France.
| | - Mans Broekgaarden
- Université Grenoble Alpes, Inserm U 1209, CNRS UMR 5309, Institute for Advanced Biosciences, 38000, Grenoble, France.
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25
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Kim E, Suh JS, Jang YK, Kim H, Choi G, Kim TJ. Harmine inhibits proliferation and migration of glioblastoma via ERK signalling. Process Biochem 2022. [DOI: 10.1016/j.procbio.2022.09.014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
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26
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CircRNA-Based Cervical Cancer Prognosis Model, Immunological Validation and Drug Prediction. Curr Oncol 2022; 29:7994-8018. [PMID: 36354693 PMCID: PMC9689098 DOI: 10.3390/curroncol29110633] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2022] [Revised: 07/19/2022] [Accepted: 08/30/2022] [Indexed: 11/06/2022] Open
Abstract
BACKGROUND Cervical cancer (CC) is a common cancer in female, which is associated with problems like poor prognosis. Circular RNA (circRNA) is a kind of competing endogenous RNA (ceRNA) that has an important role in regulating microRNA (miRNA) in many cancers. The regulatory mechanisms of CC immune microenvironment and the transcriptome level remain to be fully explored. METHODS In this study, we constructed the ceRNA network through the interaction data and expression matrix of circRNA, miRNA and mRNA. Meanwhile, based on the gene expression matrix, CIBERSORT algorithm was used to reveal contents of tumor-infiltrating immune cells (TIICs). Then, we screened prognostic markers based on ceRNA network and immune infiltration and constructed two nomograms. In order to find immunological differences between the high- and low-risk CC samples, we examined multiple immune checkpoints and predicted the effect of PD-L1 ICI immunotherapy. In addition, the sensitive therapeutics for high-risk patients were screened, and the potential agents with anti-CC activity were predicted by Connective Map (CMap). RESULTS We mapped a ceRNA network including 5 circRNAs, 17 miRNAs and 129 mRNAs. From the mRNA nodes of the network six genes and two kind of cells were identified as prognostic makers for CC. Among them, there was a significant positive correlation between CD8+ T cells and SNX10 gene. The results of TIDE and single sample GSEA (ssGSEA) showed that T cells CD8 do play a key role in inhibiting tumor progression. Further, our study screened 24 drugs that were more sensitive to high-risk CC patients and several potential therapeutic agents for reference. CONCLUSIONS Our study identified several circRNA-miRNA-mRNA regulatory axes and six prognostic genes based on the ceRNA network. In addition, through TIIC, survival analysis and a series of immunological analyses, T cells were proved to be good prognostic markers, besides play an important role in the immune process. Finally, we screened 24 potentially more effective drugs and multiple potential drug compounds for high- and low-risk patients.
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27
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Zhang S, Liu J, Lu ZY, Xue YT, Mu XR, Liu Y, Cao J, Li ZY, Li F, Xu KL, Wu QY. Combination of RSK inhibitor LJH-685 and FLT3 inhibitor FF-10101 promoted apoptosis and proliferation inhibition of AML cell lines. Cell Oncol (Dordr) 2022; 45:1005-1018. [PMID: 36036884 DOI: 10.1007/s13402-022-00703-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/09/2022] [Indexed: 11/03/2022] Open
Abstract
PURPOSE FLT3 mutations occurred in approximately one third of patients with acute myeloid leukemia (AML). FLT3-ITD mutations caused the constitutive activation of the RAS/MAPK signaling pathway. Ribosomal S6 Kinases (RSKs) were serine/threonine kinases that function downstream of the Ras/Raf/MEK/ERK signaling pathway. However, roles and mechanisms of RSKs inhibitor LJH-685, and combinational effects of LJH-685 and FLT3 inhibitor FF-10101 on AML cells were till unclear. METHODS Cell viability assay, CFSE assay, RT-qPCR, Colony formation assay, PI stain, Annexin-V/7-AAD double stain, Western blot, and Xenogeneic transplantation methods were used to used to investigate roles and mechanisms of LJH-685 in the leukemogenesis of AML. RESULTS LJH-685 inhibited the proliferation and clone formation of AML cells, caused cell cycle arrest and induced the apoptosis of AML cells via inhibiting the RSK-YB-1 signaling pathway. MV4-11 and MOLM-13 cells carrying FLT3-ITD mutations were more sensitive to LJH-685 than that of other AML cell lines. Further studies suggested that LJH-685 combined with Daunorubicin or FF- 10101 synergistically inhibited the cell viability, promoted the apoptosis and caused cycle arrest of AML cells carrying FLT3-ITD mutations. Moreover, in vivo experiments also indicated that LJH-685 combined with FF-10101 or Daunorubicin prolonged the survival time of NSG mice and reduced the leukemogenesis of AML. CONCLUSION Thus, these observations demonstrated combination of RSK inhibitor LJH-685 and FLT3 inhibitor FF-10101 showed synergism anti-leukemia effects in AML cell lines with FLT3-ITD mutations via inhibiting MAPK-RSKs-YB-1 pathway and provided new targets for therapeutic intervention especially for AML with FLT3-ITD mutations and Daunorubicin-resistant AML.
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Affiliation(s)
- Sen Zhang
- Blood Diseases Institute, Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Jun Liu
- Blood Diseases Institute, Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Zi-Yi Lu
- Blood Diseases Institute, Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Yu-Tong Xue
- Blood Diseases Institute, Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Xing-Ru Mu
- Blood Diseases Institute, Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Yang Liu
- Blood Diseases Institute, Xuzhou Medical University, Xuzhou, Jiangsu, China.,Department of Hematology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Jiang Cao
- Department of Hematology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Zhen-Yu Li
- Department of Hematology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Feng Li
- Department of Cell Biology and Neurobiology, Xuzhou Medical University, Xuzhou, 221002, People's Republic of China.
| | - Kai-Lin Xu
- Blood Diseases Institute, Xuzhou Medical University, Xuzhou, Jiangsu, China. .,Department of Hematology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, China.
| | - Qing-Yun Wu
- Blood Diseases Institute, Xuzhou Medical University, Xuzhou, Jiangsu, China. .,Department of Hematology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, China.
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28
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Huang C, Yi H, Zhou Y, Zhang Q, Yao X. Pan-Cancer Analysis Reveals SH3TC2 as an Oncogene for Colorectal Cancer and Promotes Tumorigenesis via the MAPK Pathway. Cancers (Basel) 2022; 14:3735. [PMID: 35954399 PMCID: PMC9367385 DOI: 10.3390/cancers14153735] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2022] [Revised: 07/24/2022] [Accepted: 07/26/2022] [Indexed: 12/11/2022] Open
Abstract
SH3 domain and tetrapeptide repeat 2 (SH3TC2) is a protein-encoding gene and has previously been described as a critical signaling hub for neurological disorders. Although increasing evidence supports a vital role of SH3TC2 in the tumorigenesis of various kinds of cancer, no systematic analysis of SH3TC2 is available. The function and mechanism of SH3TC2 in other cancers remain unknown. Thus, this study aimed to analyze SH3TC2 in various kinds of cancer to find its tumorigenic role in one or more specific cancers. In the current study, we analyzed the expression level and prognostic value of SH3TC2 in different tumors in the TCGA-GTEx pan-cancer dataset. Subsequently, the prognostic role and mechanism of SH3TC2 in colorectal cancer (CRC) were further explored via clinical samples and in vitro and in vivo experiments. We observed differential expression of SH3TC2 in colon adenocarcinoma (COAD), acute myeloid leukemia (LAML), READ (rectum adenocarcinoma), SKCM (skin cutaneous melanoma), and TGCT (testicular germ cell tumors). Subsequently, SH3TC2 showed a significant effect on the clinical stage and prognostic value in CRC, LAML, and SKCM. Moreover, we found in the TCGA database and seven GEO datasets that SH3TC2 was significantly highly expressed in tumor tissue. Through enrichment analysis of SH3TC2 and its co-expressed genes, we found that SH3TC2 may play a role in the MAPK signaling pathway. Correlation analysis indicated that SH3TC2 was significantly associated with multiple key factors in the MAPK signaling pathway. Additionally, higher expression of SH3TC2 was found in tumor tissue in our cohort including 40 CRC patients. Overexpression of SH3TC2 may imply poor prognosis. Knockdown of SH3TC2 significantly inhibited tumor invasion, migration, and proliferation. More importantly, knockdown of SH3TC2 inhibited tumor growth in a CRC mouse model. The study preliminarily conducted a pan-cancer study of SH3TC2 and further explored the mechanism of SH3TC2 in CRC. Our research revealed that higher expression of SH3TC2 may promote CRC progression and invasion via the MAPK signaling pathway.
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Affiliation(s)
- Chengzhi Huang
- School of Medicine, South China University of Technology, Guangzhou 510006, China;
- Department of Gastrointestinal Surgery, Department of General Surgery, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou 510080, China; (H.Y.); (Y.Z.)
- Department of General Surgery, Guangdong Provincial People’s Hospital Ganzhou Hospital (Ganzhou Municipal Hospital), Ganzhou 341000, China
| | - Hui Yi
- Department of Gastrointestinal Surgery, Department of General Surgery, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou 510080, China; (H.Y.); (Y.Z.)
- Department of General Surgery, Guangdong Provincial People’s Hospital Ganzhou Hospital (Ganzhou Municipal Hospital), Ganzhou 341000, China
- School of Biology and Biological Engineering, South China University of Technology, Guangzhou 510006, China
- Department of Pharmacology, The First People’s Hospital of Zhaoqing, Zhaoqing 526000, China
| | - Yue Zhou
- Department of Gastrointestinal Surgery, Department of General Surgery, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou 510080, China; (H.Y.); (Y.Z.)
- Department of General Surgery, Guangdong Provincial People’s Hospital Ganzhou Hospital (Ganzhou Municipal Hospital), Ganzhou 341000, China
- The Second School of Clinical Medicine, Southern Medical University, Guangzhou 510515, China
| | - Qing Zhang
- Department of General Surgery, Guangdong Provincial People’s Hospital Ganzhou Hospital (Ganzhou Municipal Hospital), Ganzhou 341000, China
- Department of Gastrointestinal and Anorectal Surgery, The First People’s Hospital of Zhaoqing, Zhaoqing 526000, China
| | - Xueqing Yao
- School of Medicine, South China University of Technology, Guangzhou 510006, China;
- Department of Gastrointestinal Surgery, Department of General Surgery, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou 510080, China; (H.Y.); (Y.Z.)
- Department of General Surgery, Guangdong Provincial People’s Hospital Ganzhou Hospital (Ganzhou Municipal Hospital), Ganzhou 341000, China
- School of Biology and Biological Engineering, South China University of Technology, Guangzhou 510006, China
- The Second School of Clinical Medicine, Southern Medical University, Guangzhou 510515, China
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29
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Gouda MB, Hassan NM, Kandil EI, Haroun RAH. Pathogenetic Significance of YBX1 Expression in Acute Myeloid Leukemia Relapse. Curr Res Transl Med 2022; 70:103336. [DOI: 10.1016/j.retram.2022.103336] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2021] [Revised: 12/26/2021] [Accepted: 01/30/2022] [Indexed: 11/03/2022]
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30
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Yen SC, Wu YW, Huang CC, Chao MW, Tu HJ, Chen LC, Lin TE, Sung TY, Tseng HJ, Chu JC, Huang WJ, Yang CR, HuangFu WC, Pan SL, Hsu KC. O-methylated flavonol as a multi-kinase inhibitor of leukemogenic kinases exhibits a potential treatment for acute myeloid leukemia. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2022; 100:154061. [PMID: 35364561 DOI: 10.1016/j.phymed.2022.154061] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/28/2021] [Revised: 03/12/2022] [Accepted: 03/14/2022] [Indexed: 06/14/2023]
Abstract
BACKGROUND Acute myeloid leukemia (AML) is a heterogeneous disease with poor overall survival characterized by various genetic changes. The continuous activation of oncogenic pathways leads to the development of drug resistance and limits current therapeutic efficacy. Therefore, a multi-targeting inhibitor may overcome drug resistance observed in AML treatment. Recently, groups of flavonoids, such as flavones and flavonols, have been shown to inhibit a variety of kinase activities, which provides potential opportunities for further anticancer applications. PURPOSE In this study, we evaluated the anticancer effects of flavonoid compounds collected from our in-house library and investigated their potential anticancer mechanisms by targeting multiple kinases for inhibition in AML cells. METHODS The cytotoxic effect of the compounds was detected by cell viability assays. The kinase inhibitory activity of the selected compound was detected by kinase-based and cell-based assays. The binding conformation and interactions were investigated by molecular docking analysis. Flow cytometry was used to evaluate the cell cycle distribution and cell apoptosis. The protein and gene expression were estimated by western blotting and qPCR, respectively. RESULTS In this study, an O-methylated flavonol (compound 11) was found to possess remarkable cytotoxic activity against AML cells compared to treatment in other cancer cell lines. The compound was demonstrated to act against multiple kinases, which play critical roles in survival signaling in AML, including FLT3, MNK2, RSK, DYRK2 and JAK2 with IC50 values of 1 - 2 μM. Compared to our previous flavonoid compounds, which only showed inhibitions against MNKs or FLT3, compound 11 exhibited multiple kinase inhibitory abilities. Moreover, compound 11 showed effectiveness in inhibiting internal tandem duplications of FLT3 (FLT3-ITDs), which accounts for 25% of AML cases. The interactions between compound 11 and targeted kinases were investigated by molecular docking analysis. Mechanically, compound 11 caused dose-dependent accumulation of leukemic cells at the G0/G1 phase and followed by the cells undergoing apoptosis. CONCLUSION O-methylated flavonol, compound 11, can target multiple kinases, which may provide potential opportunities for the development of novel therapeutics for drug-resistant AMLs. This work provides a good starting point for further compound optimization.
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Affiliation(s)
- Shih-Chung Yen
- Warshel Institute for Computational Biology, The Chinese University of Hong Kong (Shenzhen), Shenzhen, Guangdong, China
| | - Yi-Wen Wu
- Warshel Institute for Computational Biology, The Chinese University of Hong Kong (Shenzhen), Shenzhen, Guangdong, China; Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan
| | - Cheng-Chiao Huang
- Ph.D. Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University and Academia Sinica, Taipei, Taiwan; Division of General Surgery, Department of Surgery, Taipei Medical University Hospital, Taipei, Taiwan
| | - Min-Wu Chao
- School of Pharmacy, College of Medicine, National Taiwan University, Taipei, Taiwan; College of Science, National Sun Yat-sen University, Kaohsiung, Taiwan
| | - Huang-Ju Tu
- Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan
| | - Liang-Chieh Chen
- Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan; Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, United States
| | - Tony Eight Lin
- Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan; Master Program in Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan
| | - Tzu-Ying Sung
- Biomedical Translation Research Center, Academia Sinica, Taipei, Taiwan
| | - Hui-Ju Tseng
- Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, United States
| | - Jung-Chun Chu
- Ph.D. Program in Drug Discovery and Development Industry, College of Pharmacy, Taipei Medical University, Taipei, Taiwan
| | - Wei-Jan Huang
- Ph.D. Program in Drug Discovery and Development Industry, College of Pharmacy, Taipei Medical University, Taipei, Taiwan; Graduate Institute of Pharmacognosy, College of Pharmacy, Taipei Medical University, Taipei, Taiwan
| | - Chia-Ron Yang
- School of Pharmacy, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Wei-Chun HuangFu
- Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan; Ph.D. Program in Drug Discovery and Development Industry, College of Pharmacy, Taipei Medical University, Taipei, Taiwan; Ph.D. Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan; TMU Research Center of Cancer Translational Medicine, Taipei Medical University, Taipei, Taiwan
| | - Shiow-Lin Pan
- Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan; Ph.D. Program in Drug Discovery and Development Industry, College of Pharmacy, Taipei Medical University, Taipei, Taiwan; Ph.D. Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan; TMU Research Center of Cancer Translational Medicine, Taipei Medical University, Taipei, Taiwan; TMU Research Center of Drug Discovery, Taipei Medical University, Taipei, Taiwan.
| | - Kai-Cheng Hsu
- Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan; Ph.D. Program in Drug Discovery and Development Industry, College of Pharmacy, Taipei Medical University, Taipei, Taiwan; Ph.D. Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan; TMU Research Center of Cancer Translational Medicine, Taipei Medical University, Taipei, Taiwan; TMU Research Center of Drug Discovery, Taipei Medical University, Taipei, Taiwan; Cancer Center, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan.
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31
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Yuan O, Ugale A, de Marchi T, Anthonydhason V, Konturek-Ciesla A, Wan H, Eldeeb M, Drabe C, Jassinskaja M, Hansson J, Hidalgo I, Velasco-Hernandez T, Cammenga J, Magee JA, Niméus E, Bryder D. A somatic mutation in moesin drives progression into acute myeloid leukemia. SCIENCE ADVANCES 2022; 8:eabm9987. [PMID: 35442741 PMCID: PMC9020775 DOI: 10.1126/sciadv.abm9987] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/02/2021] [Accepted: 03/01/2022] [Indexed: 06/14/2023]
Abstract
Acute myeloid leukemia (AML) arises when leukemia-initiating cells, defined by a primary genetic lesion, acquire subsequent molecular changes whose cumulative effects bypass tumor suppression. The changes that underlie AML pathogenesis not only provide insights into the biology of transformation but also reveal novel therapeutic opportunities. However, backtracking these events in transformed human AML samples is challenging, if at all possible. Here, we approached this question using a murine in vivo model with an MLL-ENL fusion protein as a primary molecular event. Upon clonal transformation, we identified and extensively verified a recurrent codon-changing mutation (Arg295Cys) in the ERM protein moesin that markedly accelerated leukemogenesis. Human cancer-associated moesin mutations at the conserved arginine-295 residue similarly enhanced MLL-ENL-driven leukemogenesis. Mechanistically, the mutation interrupted the stability of moesin and conferred a neomorphic activity to the protein, which converged on enhanced extracellular signal-regulated kinase activity. Thereby, our studies demonstrate a critical role of ERM proteins in AML, with implications also for human cancer.
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Affiliation(s)
- Ouyang Yuan
- Division of Molecular Hematology, Department of Laboratory Medicine, Lund Stem Cell Center, Faculty of Medical, Lund University, 221 84 Lund, Sweden
| | - Amol Ugale
- Division of Molecular Hematology, Department of Laboratory Medicine, Lund Stem Cell Center, Faculty of Medical, Lund University, 221 84 Lund, Sweden
- Department of Microbiology, Immunobiology and Genetics, Center for Molecular Biology of the University of Vienna, Max F. Perutz Laboratories, Vienna Biocenter (VBC), 1030 Vienna, Austria
| | - Tommaso de Marchi
- Division of Surgery, Oncology, and Pathology, Department of Clinical Sciences, Lund University, Solvegatan 19, 223 62, Lund, Sweden
| | - Vimala Anthonydhason
- Sahlgrenska Center for Cancer Research, University of Gothenburg, Medicinaregatan 1F, 413 90, Gothenburg, Sweden
| | - Anna Konturek-Ciesla
- Division of Molecular Hematology, Department of Laboratory Medicine, Lund Stem Cell Center, Faculty of Medical, Lund University, 221 84 Lund, Sweden
| | - Haixia Wan
- Division of Molecular Hematology, Department of Laboratory Medicine, Lund Stem Cell Center, Faculty of Medical, Lund University, 221 84 Lund, Sweden
| | - Mohamed Eldeeb
- Division of Molecular Hematology, Department of Laboratory Medicine, Lund Stem Cell Center, Faculty of Medical, Lund University, 221 84 Lund, Sweden
| | - Caroline Drabe
- Division of Molecular Hematology, Department of Laboratory Medicine, Lund Stem Cell Center, Faculty of Medical, Lund University, 221 84 Lund, Sweden
| | - Maria Jassinskaja
- Division of Molecular Hematology, Department of Laboratory Medicine, Lund Stem Cell Center, Faculty of Medical, Lund University, 221 84 Lund, Sweden
- York Biomedical Research Institute, Department of Biology, University of York, Wentworth Way, York YO10 5DD, UK
| | - Jenny Hansson
- Division of Molecular Hematology, Department of Laboratory Medicine, Lund Stem Cell Center, Faculty of Medical, Lund University, 221 84 Lund, Sweden
| | - Isabel Hidalgo
- Division of Molecular Hematology, Department of Laboratory Medicine, Lund Stem Cell Center, Faculty of Medical, Lund University, 221 84 Lund, Sweden
| | | | - Jörg Cammenga
- Division of Molecular Hematology, Department of Laboratory Medicine, Lund Stem Cell Center, Faculty of Medical, Lund University, 221 84 Lund, Sweden
| | - Jeffrey A. Magee
- Department of Pediatrics, Division of Hematology and Oncology, Washington University School of Medicine, St. Louis, MO 63110, USA
- Department of Genetics, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Emma Niméus
- Division of Surgery, Oncology, and Pathology, Department of Clinical Sciences, Lund University, Solvegatan 19, 223 62, Lund, Sweden
- Department of Surgery, Skåne University Hospital, Entrégatan 7, 222 42 Lund, Sweden
| | - David Bryder
- Division of Molecular Hematology, Department of Laboratory Medicine, Lund Stem Cell Center, Faculty of Medical, Lund University, 221 84 Lund, Sweden
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32
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Tang X, Chen F, Xie LC, Liu SX, Mai HR. Targeting metabolism: A potential strategy for hematological cancer therapy. World J Clin Cases 2022; 10:2990-3004. [PMID: 35647127 PMCID: PMC9082716 DOI: 10.12998/wjcc.v10.i10.2990] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/15/2021] [Revised: 11/01/2021] [Accepted: 02/27/2022] [Indexed: 02/06/2023] Open
Abstract
Most hematological cancer-related relapses and deaths are caused by metastasis; thus, the importance of this process as a target of therapy should be considered. Hematological cancer is a type of cancer in which metabolism plays an essential role in progression. Therefore, we are required to block fundamental metastatic processes and develop specific preclinical and clinical strategies against those biomarkers involved in the metabolic regulation of hematological cancer cells, which do not rely on primary tumor responses. To understand progress in this field, we provide a summary of recent developments in the understanding of metabolism in hematological cancer and a general understanding of biomarkers currently used and under investigation for clinical and preclinical applications involving drug development. The signaling pathways involved in cancer cell metabolism are highlighted and shed light on how we could identify novel biomarkers involved in cancer development and treatment. This review provides new insights into biomolecular carriers that could be targeted as anticancer biomarkers.
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Affiliation(s)
- Xue Tang
- Department of Hematology and Oncology, Shenzhen Children’s Hospital, Shenzhen 518038, Guangdong Province, China
| | - Fen Chen
- Department of Hematology and Oncology, Shenzhen Children’s Hospital, Shenzhen 518038, Guangdong Province, China
| | - Li-Chun Xie
- Department of Hematology and Oncology, Shenzhen Children’s Hospital, Shenzhen 518038, Guangdong Province, China
| | - Si-Xi Liu
- Department of Hematology and Oncology, Shenzhen Children’s Hospital, Shenzhen 518038, Guangdong Province, China
| | - Hui-Rong Mai
- Department of Hematology and Oncology, Shenzhen Children’s Hospital, Shenzhen 518038, Guangdong Province, China
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Isabelle C, Boles A, Chakravarti N, Porcu P, Brammer J, Mishra A. Cytokines in the Pathogenesis of Large Granular Lymphocytic Leukemia. Front Oncol 2022; 12:849917. [PMID: 35359386 PMCID: PMC8960188 DOI: 10.3389/fonc.2022.849917] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2022] [Accepted: 02/08/2022] [Indexed: 12/25/2022] Open
Abstract
Large granular lymphocytic leukemia (LGLL) is a lymphoproliferative disorder of older adults characterized by the clonal expansion of cytotoxic T/natural killer cells due to constitutive pro-survival signaling. In recent years, it has become clear that cytokines and their receptors are aberrantly expressed in LGLL cells. The exact initiation process of LGLL is unknown, although several cytokine-driven mechanisms have emerged. Elevated levels of several cytokines, including interleukin-15 (IL-15) and platelet-derived growth factor (PDGF), have been described in LGLL patients. Evidence from humans and animal models has shown that cytokines may also contribute to the co-occurrence of a wide range of autoimmune diseases seen in patients with LGLL. The goal of this review is to provide a comprehensive analysis of the link between cytokines and pro-survival signaling in LGLL and to discuss the various strategies and research approaches that are being utilized to study this link. This review will also highlight the importance of cytokine-targeted therapeutics in the treatment of LGLL.
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Affiliation(s)
- Colleen Isabelle
- Division of Hematologic Malignancies and Hematopoietic Stem Cell Transplantation, Department of Medical Oncology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, United States
| | - Amy Boles
- Division of Hematologic Malignancies and Hematopoietic Stem Cell Transplantation, Department of Medical Oncology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, United States
| | - Nitin Chakravarti
- Division of Hematologic Malignancies and Hematopoietic Stem Cell Transplantation, Department of Medical Oncology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, United States
| | - Pierluigi Porcu
- Division of Hematologic Malignancies and Hematopoietic Stem Cell Transplantation, Department of Medical Oncology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, United States
| | - Jonathan Brammer
- Division of Hematology, The Ohio State University, Columbus, OH, United States
| | - Anjali Mishra
- Division of Hematologic Malignancies and Hematopoietic Stem Cell Transplantation, Department of Medical Oncology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, United States
- Department of Cancer Biology, Sidney Kimmel Cancer Center, Philadelphia, PA, United States
- *Correspondence: Anjali Mishra,
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Analysis of 5-Azacytidine Resistance Models Reveals a Set of Targetable Pathways. Cells 2022; 11:cells11020223. [PMID: 35053339 PMCID: PMC8774143 DOI: 10.3390/cells11020223] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2021] [Revised: 01/04/2022] [Accepted: 01/07/2022] [Indexed: 01/27/2023] Open
Abstract
The mechanisms by which myelodysplastic syndrome (MDS) cells resist the effects of hypomethylating agents (HMA) are currently the subject of intensive research. A better understanding of mechanisms by which the MDS cell becomes to tolerate HMA and progresses to acute myeloid leukemia (AML) requires the development of new cellular models. From MDS/AML cell lines we developed a model of 5-azacytidine (AZA) resistance whose stability was validated by a transplantation approach into immunocompromised mice. When investigating mRNA expression and DNA variants of the AZA resistant phenotype we observed deregulation of several cancer-related pathways including the phosphatidylinosito-3 kinase signaling. We have further shown that these pathways can be modulated by specific inhibitors that, while blocking the proliferation of AZA resistant cells, are unable to increase their sensitivity to AZA. Our data reveal a set of molecular mechanisms that can be targeted to expand therapeutic options during progression on AZA therapy.
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Leotta S, Condorelli A, Sciortino R, Milone GA, Bellofiore C, Garibaldi B, Schininà G, Spadaro A, Cupri A, Milone G. Prevention and Treatment of Acute Myeloid Leukemia Relapse after Hematopoietic Stem Cell Transplantation: The State of the Art and Future Perspectives. J Clin Med 2022; 11:253. [PMID: 35011994 PMCID: PMC8745746 DOI: 10.3390/jcm11010253] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2021] [Revised: 12/24/2021] [Accepted: 12/28/2021] [Indexed: 12/19/2022] Open
Abstract
Allogeneic hematopoietic stem cell transplantation (HSCT) for high-risk acute myeloid leukemia (AML) represents the only curative option. Progress has been made in the last two decades in the pre-transplant induction therapies, supportive care, selection of donors and conditioning regimens that allowed to extend the HSCT to a larger number of patients, including those aged over 65 years and/or lacking an HLA-identical donor. Furthermore, improvements in the prophylaxis of the graft-versus-host disease and of infection have dramatically reduced transplant-related mortality. The relapse of AML remains the major reason for transplant failure affecting almost 40-50% of the patients. From 10 to 15 years ago to date, treatment options for AML relapsing after HSCT were limited to conventional cytotoxic chemotherapy and donor leukocyte infusions (DLI). Nowadays, novel agents and targeted therapies have enriched the therapeutic landscape. Moreover, very recently, the therapeutic landscape has been enriched by manipulated cellular products (CAR-T, CAR-CIK, CAR-NK). In light of these new perspectives, careful monitoring of minimal-residual disease (MRD) and prompt application of pre-emptive strategies in the post-transplant setting have become imperative. Herein, we review the current state of the art on monitoring, prevention and treatment of relapse of AML after HSCT with particular attention on novel agents and future directions.
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Affiliation(s)
| | - Annalisa Condorelli
- Division of Hematology, AOU “Policlinico G. Rodolico-San Marco”, Via Santa Sofia 78, 95124 Catania, Italy; (S.L.); (R.S.); (G.A.M.); (C.B.); (B.G.); (G.S.); (A.S.); (A.C.); (G.M.)
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36
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Khader A, Bokhari R, Hakimelahi R, Scheirey C, Afnan J, Braschi-Amirfarzan M, Thomas R. A radiologist’s guide to novel anticancer therapies in the era of precision medicine. Eur J Radiol Open 2022; 9:100406. [PMID: 35265736 PMCID: PMC8899228 DOI: 10.1016/j.ejro.2022.100406] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2021] [Revised: 02/14/2022] [Accepted: 02/15/2022] [Indexed: 12/13/2022] Open
Abstract
Novel anticancer agents have replaced conventional chemotherapy as first line agents for many cancers, with continued new and expanding indications. Small molecule inhibitors act on cell surface or intracellular targets and prevent the downstream signaling that would otherwise permit tumor growth and spread. Anticancer antibodies can be directed against growth factors or may be immunotherapeutic agents. The latter act by inhibiting mechanisms that cancer cells use to evade the immune system. Hormonal agents act by decreasing levels of hormones that are necessary for the growth of certain cancer cells. Cancer therapy protocols often include novel anticancer agents and conventional chemotherapy used successively or in combination, in order to maximize survival and minimize morbidity. A working knowledge of anti-cancer drug classification will aid the radiologist in assessing response on imaging.
Novel anticancer agents include small molecule inhibitors, antibodies and hormones. These agents are predominantly cytostatic and inhibit factors that provide a survival advantage to tumor cells. Modern cancer therapy employs a combination of novel anticancer agents and conventional chemotherapy. It is essential for radiologists to have a broad understanding of these agents and their mechanisms of action.
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37
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Fumagalli G, Carbajo RJ, Nissink JWM, Tart J, Dou R, Thomas AP, Spring DR. Targeting a Novel KRAS Binding Site: Application of One-Component Stapling of Small (5-6-mer) Peptides. J Med Chem 2021; 64:17287-17303. [PMID: 34787423 DOI: 10.1021/acs.jmedchem.1c01334] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
RAS proteins are central in the proliferation of many types of cancer, but a general approach toward the identification of pan-mutant RAS inhibitors has remained unresolved. In this work, we describe the application of a binding pharmacophore identified from analysis of known RAS binding peptides to the design of novel peptides. Using a chemically divergent approach, we generated a library of small stapled peptides from which we identified compounds with weak binding activity. Exploration of structure-activity relationships (SARs) and optimization of these early compounds led to low-micromolar binders of KRAS that block nucleotide exchange.
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Affiliation(s)
- Gabriele Fumagalli
- Department of Chemistry, Cambridge University, Lensfield Road, Cambridge CB2 1EW, U.K.,Chemistry, Oncology R&D, AstraZeneca, Cambridge CB4 0WG, U.K
| | | | | | - Jonathan Tart
- Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Cambridge CB4 0WG, U.K
| | - Rongxuan Dou
- Department of Chemistry, Cambridge University, Lensfield Road, Cambridge CB2 1EW, U.K
| | - Andrew P Thomas
- Chemistry, Oncology R&D, AstraZeneca, Cambridge CB4 0WG, U.K
| | - David R Spring
- Department of Chemistry, Cambridge University, Lensfield Road, Cambridge CB2 1EW, U.K
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K-RAS Acts as a Critical Regulator of CD44 to Promote the Invasiveness and Stemness of GBM in Response to Ionizing Radiation. Int J Mol Sci 2021; 22:ijms222010923. [PMID: 34681583 PMCID: PMC8539357 DOI: 10.3390/ijms222010923] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2021] [Revised: 10/04/2021] [Accepted: 10/05/2021] [Indexed: 12/21/2022] Open
Abstract
Radiation therapy is a current standard-of-care treatment and is used widely for GBM patients. However, radiation therapy still remains a significant barrier to getting a successful outcome due to the therapeutic resistance and tumor recurrence. Understanding the underlying mechanisms of this resistance and recurrence would provide an efficient approach for improving the therapy for GBM treatment. Here, we identified a regulatory mechanism of CD44 which induces infiltration and mesenchymal shift of GBM. Ionizing radiation (IR)-induced K-RAS/ERK signaling activation elevates CD44 expression through downregulation of miR-202 and miR-185 expression. High expression of CD44 promotes SRC activation to induce cancer stemness and EMT features of GBM cells. In this study, we demonstrate that the K-RAS/ERK/CD44 axis is a key mechanism in regulating mesenchymal shift of GBM cells after irradiation. These findings suggest that blocking the K-RAS activation or CD44 expression could provide an efficient way for GBM treatment.
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39
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Small-molecule inhibitor targeting the Hsp70-Bim protein-protein interaction in CML cells overcomes BCR-ABL-independent TKI resistance. Leukemia 2021; 35:2862-2874. [PMID: 34007045 DOI: 10.1038/s41375-021-01283-5] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2021] [Revised: 04/21/2021] [Accepted: 05/04/2021] [Indexed: 02/06/2023]
Abstract
Herein, we screened a novel inhibitor of the Hsp70-Bim protein-protein interaction (PPI), S1g-2, from a Bcl-2 inhibitor library; this compound specifically disrupted the Hsp70-Bim PPI by direct binding to an unknown site adjacent to that of an allosteric Hsp70 inhibitor MKT-077, showing binding affinity in sub-μM concentration range. S1g-2 exhibited overall 5-10-fold higher apoptosis-inducing activity in CML cells, primary CML blasts, and BCR-ABL-transformed BaF3 cells than other cancer cells, normal lymphocytes, and BaF3 cells, illustrating Hsp70-Bim PPI driven by BCR-ABL protects CML through oncoclient proteins that enriched in three pathways: eIF2 signaling, the regulation of eIF4E and p70S6K signaling, and the mTOR signaling pathways. Moreover, S1g-2 progressively enhanced lethality along with the increase in BCR-ABL-independent TKI resistance in the K562 cell lines and is more effective in primary samples from BCR-ABL-independent TKI-resistant patients than those from TKI-sensitive patients. By comparing the underlying mechanisms of S1g-2, MKT-077, and an ATP-competitive Hsp70 inhibitor VER-155008, the Hsp70-Bim PPI was identified to be a CML-specific target to protect from TKIs through the above three oncogenic signaling pathways. The in vivo activity against CML and low toxicity endows S1g-2 a first-in-class promising drug candidate for both TKI-sensitive and resistant CML.
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40
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Park J, Park H, Byun JM, Hong J, Shin DY, Koh Y, Yoon SS. Pan-RAF inhibitor LY3009120 is highly synergistic with low-dose cytarabine, but not azacitidine, in acute myeloid leukemia with RAS mutations. Oncol Lett 2021; 22:745. [PMID: 34539849 DOI: 10.3892/ol.2021.13006] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2021] [Accepted: 07/26/2021] [Indexed: 11/06/2022] Open
Abstract
Alterations in RAS oncogenes have been implicated in various types of cancer, including acute myeloid leukemia (AML). Considering that currently, there are no targeted therapies for patients with RAS-mutated AML despite the poor outcomes, RAF may be a potential target for AML. In this study, we first analyzed the efficacy of different MAPK inhibitors in AML cell lines. We found that LY3009120, a pan-RAF inhibitor, significantly decreased cell survival in RAS-mutated AML cell lines. We then investigated the synergistic effects of LY3009120 with either cytarabine or azacitidine. We found that the combination of low-dose cytarabine and LY3009120 showed a synergistic effect in NRAS-mutated HL-60 cells and KRAS-mutated NB4 cells. This effect was caused by a decrease in proliferation, induction of apoptosis, and cell growth arrest through a decrease in phosphorylated MEK and ERK along with a cytotoxic response occurring specifically for the RAS mutation of the pan-RAF inhibitor LY3009120. In addition, we confirmed that combination treatment with low-dose cytarabine and LY3009120 led to an increase in apoptosis in primary AML cells. Our findings indicate that combination therapy with pan-RAF inhibitor LY3009120 and low-dose cytarabine may be a promising treatment strategy for RAS-mutated AML.
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Affiliation(s)
- Jihyun Park
- Cancer Research Institute, Seoul National University College of Medicine, Seoul 03080, Republic of Korea.,Hematology Oncology Department, Center for Medical Innovation, Seoul National University Hospital, Seoul 03082, Republic of Korea
| | - Hyejoo Park
- Cancer Research Institute, Seoul National University College of Medicine, Seoul 03080, Republic of Korea.,Hematology Oncology Department, Center for Medical Innovation, Seoul National University Hospital, Seoul 03082, Republic of Korea
| | - Ja Min Byun
- Department of Internal Medicine, Division of Hematology and Medical Oncology, Seoul National University Hospital, Seoul 03080, Republic of Korea
| | - Junshik Hong
- Cancer Research Institute, Seoul National University College of Medicine, Seoul 03080, Republic of Korea.,Hematology Oncology Department, Center for Medical Innovation, Seoul National University Hospital, Seoul 03082, Republic of Korea.,Department of Internal Medicine, Division of Hematology and Medical Oncology, Seoul National University Hospital, Seoul 03080, Republic of Korea
| | - Dong-Yeop Shin
- Hematology Oncology Department, Center for Medical Innovation, Seoul National University Hospital, Seoul 03082, Republic of Korea.,Department of Internal Medicine, Division of Hematology and Medical Oncology, Seoul National University Hospital, Seoul 03080, Republic of Korea
| | - Youngil Koh
- Cancer Research Institute, Seoul National University College of Medicine, Seoul 03080, Republic of Korea.,Hematology Oncology Department, Center for Medical Innovation, Seoul National University Hospital, Seoul 03082, Republic of Korea.,Department of Internal Medicine, Division of Hematology and Medical Oncology, Seoul National University Hospital, Seoul 03080, Republic of Korea
| | - Sung-Soo Yoon
- Cancer Research Institute, Seoul National University College of Medicine, Seoul 03080, Republic of Korea.,Hematology Oncology Department, Center for Medical Innovation, Seoul National University Hospital, Seoul 03082, Republic of Korea.,Department of Internal Medicine, Division of Hematology and Medical Oncology, Seoul National University Hospital, Seoul 03080, Republic of Korea
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Peng Y, Tao H, Gao Y, Yang Y, Chen Z. Review and Prospect of Tissue-agnostic Targeted Strategies in Anticancer Therapies. Curr Top Med Chem 2021; 21:404-425. [PMID: 32543358 DOI: 10.2174/1568026620666200616143247] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2020] [Revised: 05/04/2020] [Accepted: 05/08/2020] [Indexed: 11/22/2022]
Abstract
Due to the increasing prevalence of cancer year by year, and the complexity and refractory nature of the disease itself, it is required to constantly innovate the development of new cancer treatment schemes. At the same time, the understanding of cancers has deepened, from the use of chemotherapy regimens with high toxicity and side effects, to the popularity of targeted drugs with specific targets, to precise treatments based on tumor characteristics rather than traditional anatomical location classification. In precision medicine, in the view of the specific cancer diseases and their biological characteristics, there is a great potential to develop tissue-agnostic targeted therapy with broad-spectrum anticancer significance. The present review has discussed tissue-agnostic targeted therapy based on the biological and genetic characteristics of cancers, expounded its theoretical basis and strategies for drug development. In addition, the feasible drug targets, FDA-approved drugs, as well as drug candidates in clinical trials have also been summarized. In conclusion, the "tissue-agnostic targeted therapy" is a breakthrough in anticancer therapies.
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Affiliation(s)
- Yu Peng
- Jiangsu Provincial Key Laboratory of Cardiovascular and Cerebrovascular Medicine, School of Pharmacy, Nanjing Medical University, Nanjing 211166, China
| | - Hongxun Tao
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao SAR, China
| | - Yuanqing Gao
- Jiangsu Provincial Key Laboratory of Cardiovascular and Cerebrovascular Medicine, School of Pharmacy, Nanjing Medical University, Nanjing 211166, China
| | - Yuanyuan Yang
- Xi'an Institute for Food and Drug Control, Xi'an Shaanxi 710054, China
| | - Zhiyong Chen
- Shaanxi Academy of Traditional Chinese Medicine, Xi'an Shaanxi 710003, China
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42
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Pons M, Zeyn Y, Zahn S, Mahendrarajah N, Page BDG, Gunning PT, Moriggl R, Brenner W, Butter F, Krämer OH. Oncogenic Kinase Cascades Induce Molecular Mechanisms That Protect Leukemic Cell Models from Lethal Effects of De Novo dNTP Synthesis Inhibition. Cancers (Basel) 2021; 13:3464. [PMID: 34298678 PMCID: PMC8304262 DOI: 10.3390/cancers13143464] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2021] [Revised: 07/07/2021] [Accepted: 07/08/2021] [Indexed: 01/15/2023] Open
Abstract
The ribonucleotide reductase inhibitor hydroxyurea suppresses de novo dNTP synthesis and attenuates the hyperproliferation of leukemic blasts. Mechanisms that determine whether cells undergo apoptosis in response to hydroxyurea are ill-defined. We used unbiased proteomics to uncover which pathways control the transition of the hydroxyurea-induced replication stress into an apoptotic program in chronic and acute myeloid leukemia cells. We noted a decrease in the serine/threonine kinase RAF1/c-RAF in cells that undergo apoptosis in response to clinically relevant doses of hydroxyurea. Using the RAF inhibitor LY3009120, we show that RAF activity determines the sensitivity of leukemic cells toward hydroxyurea. We further disclose that pharmacological inhibition of the RAF downstream target BCL-XL with the drug navitoclax and RNAi combine favorably with hydroxyurea against leukemic cells. BCR-ABL1 and hyperactive FLT3 are tyrosine kinases that causally contribute to the development of leukemia and induce RAF1 and BCL-XL. Accordingly, the ABL inhibitor imatinib and the FLT3 inhibitor quizartinib sensitize leukemic cells to pro-apoptotic effects of hydroxyurea. Moreover, hydroxyurea and navitoclax kill leukemic cells with mutant FLT3 that are resistant to quizartinib. These data reveal cellular susceptibility factors toward hydroxyurea and how they can be exploited to eliminate difficult-to-treat leukemic cells with clinically relevant drug combinations.
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Affiliation(s)
- Miriam Pons
- Department of Toxicology, University Medical Center, 55131 Mainz, Germany; (Y.Z.); (S.Z.); (N.M.)
| | - Yanira Zeyn
- Department of Toxicology, University Medical Center, 55131 Mainz, Germany; (Y.Z.); (S.Z.); (N.M.)
| | - Stella Zahn
- Department of Toxicology, University Medical Center, 55131 Mainz, Germany; (Y.Z.); (S.Z.); (N.M.)
| | - Nisintha Mahendrarajah
- Department of Toxicology, University Medical Center, 55131 Mainz, Germany; (Y.Z.); (S.Z.); (N.M.)
| | - Brent D. G. Page
- Faculty of Pharmaceutical Science, University of British Columbia, Vancouver, BC V6T 1Z4, Canada;
| | - Patrick T. Gunning
- Department of Chemical & Physical Sciences, University of Toronto, Mississauga, ON L5L 1C6, Canada;
- Department of Chemistry, University of Toronto, Toronto, ON M5S 3H6, Canada
| | - Richard Moriggl
- Institute of Animal Breeding and Genetics, University of Veterinary Medicine, 1210 Vienna, Austria;
| | - Walburgis Brenner
- Clinic for Obstetrics and Women’s Health, University Medical Center, 55131 Mainz, Germany;
| | - Falk Butter
- Institute of Molecular Biology (IMB), 55128 Mainz, Germany;
| | - Oliver H. Krämer
- Department of Toxicology, University Medical Center, 55131 Mainz, Germany; (Y.Z.); (S.Z.); (N.M.)
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Yao Y, Li F, Huang J, Jin J, Wang H. Leukemia stem cell-bone marrow microenvironment interplay in acute myeloid leukemia development. Exp Hematol Oncol 2021; 10:39. [PMID: 34246314 PMCID: PMC8272391 DOI: 10.1186/s40164-021-00233-2] [Citation(s) in RCA: 48] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2021] [Accepted: 07/02/2021] [Indexed: 12/18/2022] Open
Abstract
Despite the advances in intensive chemotherapy regimens and targeted therapies, overall survival (OS) of acute myeloid leukemia (AML) remains unfavorable due to inevitable chemotherapy resistance and high relapse rate, which mainly caused by the persistence existence of leukemia stem cells (LSCs). Bone marrow microenvironment (BMM), the home of hematopoiesis, has been considered to play a crucial role in both hematopoiesis and leukemogenesis. When interrupted by the AML cells, a malignant BMM formed and thus provided a refuge for LSCs and protecting them from the cytotoxic effects of chemotherapy. In this review, we summarized the alterations in the bidirectional interplay between hematopoietic cells and BMM in the normal/AML hematopoietic environment, and pointed out the key role of these alterations in pathogenesis and chemotherapy resistance of AML. Finally, we focused on the current potential BMM-targeted strategies together with future prospects and challenges. Accordingly, while further research is necessary to elucidate the underlying mechanisms behind LSC–BMM interaction, targeting the interaction is perceived as a potential therapeutic strategy to eradicate LSCs and ultimately improve the outcome of AML.
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Affiliation(s)
- Yiyi Yao
- Department of Hematology, The First Affiliated Hospital, College of Medicine, Zhejiang University, 79 Qingchun Road, Hangzhou, 310003, Zhejiang, People's Republic of China.,Zhejiang Provincial Key Lab of Hematopoietic Malignancy, Zhejiang University, Hangzhou, 310003, Zhejiang, People's Republic of China
| | - Fenglin Li
- Department of Hematology, The First Affiliated Hospital, College of Medicine, Zhejiang University, 79 Qingchun Road, Hangzhou, 310003, Zhejiang, People's Republic of China.,Zhejiang Provincial Key Lab of Hematopoietic Malignancy, Zhejiang University, Hangzhou, 310003, Zhejiang, People's Republic of China
| | - Jiansong Huang
- Department of Hematology, The First Affiliated Hospital, College of Medicine, Zhejiang University, 79 Qingchun Road, Hangzhou, 310003, Zhejiang, People's Republic of China.,Zhejiang Provincial Key Lab of Hematopoietic Malignancy, Zhejiang University, Hangzhou, 310003, Zhejiang, People's Republic of China
| | - Jie Jin
- Department of Hematology, The First Affiliated Hospital, College of Medicine, Zhejiang University, 79 Qingchun Road, Hangzhou, 310003, Zhejiang, People's Republic of China. .,Zhejiang Provincial Key Lab of Hematopoietic Malignancy, Zhejiang University, Hangzhou, 310003, Zhejiang, People's Republic of China. .,Zhejiang Laboratory for Systems & Precision Medicine, Zhejiang University Medical Center, Hangzhou, 310000, Zhejiang, People's Republic of China.
| | - Huafeng Wang
- Department of Hematology, The First Affiliated Hospital, College of Medicine, Zhejiang University, 79 Qingchun Road, Hangzhou, 310003, Zhejiang, People's Republic of China. .,Zhejiang Provincial Key Lab of Hematopoietic Malignancy, Zhejiang University, Hangzhou, 310003, Zhejiang, People's Republic of China. .,Zhejiang Laboratory for Systems & Precision Medicine, Zhejiang University Medical Center, Hangzhou, 310000, Zhejiang, People's Republic of China.
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Sarkar MK, Kar A, Jayaraman A, Kar Mahapatra S, Vadivel V. Vitexin isolated from Prosopis cineraria leaves induce apoptosis in K-562 leukemia cells via inhibition of the BCR-ABL-Ras-Raf pathway. J Pharm Pharmacol 2021; 74:103-111. [PMID: 34109977 DOI: 10.1093/jpp/rgab085] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2020] [Accepted: 05/14/2021] [Indexed: 12/24/2022]
Abstract
OBJECTIVES Leukemia is one of the severe cancer types all around the globe. Even though some chemotherapeutic drugs are available for treating leukemia, they have various side effects. As an alternative approach, herbal drugs are focused on current research to overcome leukemia. The present work was conducted to investigate the antileukemic mechanism of active phytochemical vitexin, which was isolated from ethno-medicine (Prosopis cineraria leaf) used by traditional healers of West Bengal, India. METHODS Antiproliferative mechanisms of selected phyto-compound against K-562 cells were evaluated using cellular uptake, morphological changes, DNA fragmentation, mitochondrial membrane potential and signaling pathways analysis. KEY FINDINGS Vitexin exhibited cytotoxicity by reducing mitochondrial membrane potential (32.40%) and causing DNA fragmentation (84.15%). The western blotting study indicated inhibition of cell survival proteins (BCR, ABL, H-RAS, N-RAS, K-RAS and RAF) and expression of apoptotic proteins (p38, BAX and caspase-9) in leukemia cells upon treatment with vitexin. CONCLUSIONS Based on the results, presently investigated phyto-compound vitexin could be considered for developing safe and natural drugs to treat leukemia after conducting suitable preclinical and clinical trials.
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Affiliation(s)
- Monaj Kumar Sarkar
- Chemical Biology Lab (ASK-II-409), School of Chemical and Biotechnology (SCBT), SASTRA Deemed University, Thanjavur, India
| | - Amrita Kar
- Medicinal Chemistry and Immunology Lab (ASK-II-406), School of Chemical and Biotechnology (SCBT), SASTRA Deemed University, Thanjavur, India
| | - Adithyan Jayaraman
- Medicinal Chemistry and Immunology Lab (ASK-II-406), School of Chemical and Biotechnology (SCBT), SASTRA Deemed University, Thanjavur, India
| | - Santanu Kar Mahapatra
- Medicinal Chemistry and Immunology Lab (ASK-II-406), School of Chemical and Biotechnology (SCBT), SASTRA Deemed University, Thanjavur, India
| | - Vellingiri Vadivel
- Chemical Biology Lab (ASK-II-409), School of Chemical and Biotechnology (SCBT), SASTRA Deemed University, Thanjavur, India
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Wu YW, Chao MW, Tu HJ, Chen LC, Hsu KC, Liou JP, Yang CR, Yen SC, HuangFu WC, Pan SL. A novel dual HDAC and HSP90 inhibitor, MPT0G449, downregulates oncogenic pathways in human acute leukemia in vitro and in vivo. Oncogenesis 2021; 10:39. [PMID: 33986242 PMCID: PMC8119482 DOI: 10.1038/s41389-021-00331-0] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2020] [Revised: 04/07/2021] [Accepted: 04/21/2021] [Indexed: 01/06/2023] Open
Abstract
Acute leukemia is a highly heterogeneous disease; therefore, combination therapy is commonly used for patient treatment. Drug–drug interaction is a major concern of combined therapy; hence, dual/multi-target inhibitors have become a dominant approach for cancer drug development. HDACs and HSP90 are involved in the activation of various oncogenic signaling pathways, including PI3K/AKT/mTOR, JAK/STAT, and RAF/MEK/ERK, which are also highly enriched in acute leukemia gene expression profiles. Therefore, we suggest that dual HDAC and HSP90 inhibitors could represent a novel therapeutic approach for acute leukemia. MPT0G449 is a dual effect inhibitor, and it showed cytotoxic effectiveness in acute leukemia cells. Molecular docking analysis indicated that MPT0G449 possessed dual HDAC and HSP90 inhibitory abilities. Furthermore, MPT0G449 induced G2 arrest and caspase-mediated cell apoptosis in acute leukemia cells. The oncogenic signaling molecules AKT, mTOR, STAT3, STAT5, MEK, and ERK were significantly downregulated after MPT0G449 treatment in HL-60 and MOLT-4 cells. In vivo xenograft models confirmed the antitumor activity and showed the upregulation of acetyl-histone H3 and HSP70, biomarkers of pan-HDAC and HSP90 inhibition, with MPT0G449 treatment. These findings suggest that the dual inhibition of HDAC and HSP90 can suppress the expression of oncogenic pathways in acute leukemia, and MPT0G449 represents a novel therapeutic for anticancer treatment.
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Affiliation(s)
- Yi-Wen Wu
- Ph.D. Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University and Academia Sinica, Taipei, Taiwan
| | - Min-Wu Chao
- Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.,School of Pharmacy, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Huang-Ju Tu
- Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan
| | - Liang-Chieh Chen
- Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.,Warshel Institute for Computational Biology, The Chinese University of Hong Kong, Shenzhen, Guangdong, P. R. China
| | - Kai-Cheng Hsu
- Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.,Ph.D. Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.,Ph.D. Program in Drug Discovery and Development Industry, College of Pharmacy, Taipei Medical University, Taipei, Taiwan.,TMU Biomedical Commercialization Center, Taipei Medical University, Taipei, Taiwan.,TMU Research Center of Cancer Translational Medicine, Taipei Medical University, Taipei, Taiwan
| | - Jing-Ping Liou
- TMU Biomedical Commercialization Center, Taipei Medical University, Taipei, Taiwan.,School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei, Taiwan
| | - Chia-Ron Yang
- School of Pharmacy, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Shih-Chung Yen
- School of Life and Health Sciences, The Chinese University of Hong Kong, Shenzhen, Guangdong, P. R. China
| | - Wei-Chun HuangFu
- Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan. .,Ph.D. Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan. .,Ph.D. Program in Drug Discovery and Development Industry, College of Pharmacy, Taipei Medical University, Taipei, Taiwan. .,TMU Research Center of Cancer Translational Medicine, Taipei Medical University, Taipei, Taiwan.
| | - Shiow-Lin Pan
- Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan. .,Ph.D. Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan. .,Ph.D. Program in Drug Discovery and Development Industry, College of Pharmacy, Taipei Medical University, Taipei, Taiwan. .,TMU Biomedical Commercialization Center, Taipei Medical University, Taipei, Taiwan. .,TMU Research Center of Cancer Translational Medicine, Taipei Medical University, Taipei, Taiwan.
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PlatyphyllenoneExerts Anti-Metastatic Effects on Human Oral Cancer Cells by Modulating Cathepsin L Expression, MAPK Pathway and Epithelial-Mesenchymal Transition. Int J Mol Sci 2021; 22:ijms22095012. [PMID: 34065077 PMCID: PMC8125947 DOI: 10.3390/ijms22095012] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2021] [Revised: 05/04/2021] [Accepted: 05/05/2021] [Indexed: 12/13/2022] Open
Abstract
Advanced-stage oral cancers with lymph node metastasis are associated with poor prognosis and a high mortality rate. Although recent advancement in cancer treatment has effectively improved the oral cancer prognosis, the majority of therapeutic interventions are highly expensive and are associated with severe sideeffects. In the present study, we studied the efficacy of a diarylheptanoid derivative, platyphyllenone, in modulating the metastatic potential of human oral cancer cells. Specifically, we treated the human oral cancer cells (FaDu, Ca9-22, and HSC3) with different concentrations of platyphyllenone and measured the cell proliferation, migration, and invasion. The study findings revealed that platyphyllenonesignificantly inhibited the motility, migration, and invasion of human oral cancer cells. Mechanistically, platyphyllenone reduced p38 phosphorylation, decreased β-catenin and Slug, increased E-cadherin expression, and reduced cathepsin L expression, which collectively led to a reduction in cancer cell migration and invasion. Taken together, our study indicates that platyphyllenone exerts significant anti-metastatic effects on oral cancer cells by modulating cathepsin L expression, the MAPK signaling pathway, and the epithelial-mesenchymal transition process.
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Schleiss C, Carapito R, Fornecker LM, Muller L, Paul N, Tahar O, Pichot A, Tavian M, Nicolae A, Miguet L, Mauvieux L, Herbrecht R, Cianferani S, Freund JN, Carapito C, Maumy-Bertrand M, Bahram S, Bertrand F, Vallat L. Temporal multiomic modeling reveals a B-cell receptor proliferative program in chronic lymphocytic leukemia. Leukemia 2021; 35:1463-1474. [PMID: 33833385 PMCID: PMC8102193 DOI: 10.1038/s41375-021-01221-5] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2020] [Revised: 02/21/2021] [Accepted: 03/09/2021] [Indexed: 02/02/2023]
Abstract
B-cell receptor (BCR) signaling is crucial for the pathophysiology of most mature B-cell lymphomas/leukemias and has emerged as a therapeutic target whose effectiveness remains limited by the occurrence of mutations. Therefore, deciphering the cellular program activated downstream this pathway has become of paramount importance for the development of innovative therapies. Using an original ex vivo model of BCR-induced proliferation of chronic lymphocytic leukemia cells, we generated 108 temporal transcriptional and proteomic profiles from 1 h up to 4 days after BCR activation. This dataset revealed a structured temporal response composed of 13,065 transcripts and 4027 proteins, comprising a leukemic proliferative signature consisting of 430 genes and 374 proteins. Mathematical modeling of this complex cellular response further highlighted a transcriptional network driven by 14 early genes linked to proteins involved in cell proliferation. This group includes expected genes (EGR1/2, NF-kB) and genes involved in NF-kB signaling modulation (TANK, ROHF) and immune evasion (KMO, IL4I1) that have not yet been associated with leukemic cells proliferation. Our study unveils the BCR-activated proliferative genetic program in primary leukemic cells. This approach combining temporal measurements with modeling allows identifying new putative targets for innovative therapy of lymphoid malignancies and also cancers dependent on ligand-receptor interactions.
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Affiliation(s)
- Cedric Schleiss
- Laboratoire d'ImmunoRhumatologie Moléculaire, INSERM UMR-S1109, LabEx Transplantex, Plateforme Genomax, Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg, Strasbourg, France
- Fédération Hospitalo-Universitaire (FHU) Omicare, Université de Strasbourg, Strasbourg, France
| | - Raphael Carapito
- Laboratoire d'ImmunoRhumatologie Moléculaire, INSERM UMR-S1109, LabEx Transplantex, Plateforme Genomax, Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg, Strasbourg, France
- Fédération Hospitalo-Universitaire (FHU) Omicare, Université de Strasbourg, Strasbourg, France
- Laboratoire d'Immunologie, Plateau Technique de Biologie, Pôle de Biologie, Nouvel Hôpital Civil, Strasbourg, France
| | - Luc-Matthieu Fornecker
- Université de Strasbourg, INSERM, IRFAC UMR-S1113, Strasbourg, France
- Service d'Hématologie, Institut de Cancérologie Strasbourg Europe (ICANS), Strasbourg, France
| | - Leslie Muller
- Laboratoire de Spectrométrie de Masse BioOrganique, Université de Strasbourg, CNRS, IPHC, UMR 7178, Strasbourg, France
| | - Nicodème Paul
- Laboratoire d'ImmunoRhumatologie Moléculaire, INSERM UMR-S1109, LabEx Transplantex, Plateforme Genomax, Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg, Strasbourg, France
- Fédération Hospitalo-Universitaire (FHU) Omicare, Université de Strasbourg, Strasbourg, France
| | - Ouria Tahar
- Laboratoire d'ImmunoRhumatologie Moléculaire, INSERM UMR-S1109, LabEx Transplantex, Plateforme Genomax, Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg, Strasbourg, France
- Fédération Hospitalo-Universitaire (FHU) Omicare, Université de Strasbourg, Strasbourg, France
- Laboratoire d'Immunologie, Plateau Technique de Biologie, Pôle de Biologie, Nouvel Hôpital Civil, Strasbourg, France
| | - Angelique Pichot
- Laboratoire d'ImmunoRhumatologie Moléculaire, INSERM UMR-S1109, LabEx Transplantex, Plateforme Genomax, Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg, Strasbourg, France
- Fédération Hospitalo-Universitaire (FHU) Omicare, Université de Strasbourg, Strasbourg, France
| | - Manuela Tavian
- Université de Strasbourg, INSERM, IRFAC UMR-S1113, Strasbourg, France
| | - Alina Nicolae
- Université de Strasbourg, INSERM, IRFAC UMR-S1113, Strasbourg, France
| | - Laurent Miguet
- Université de Strasbourg, INSERM, IRFAC UMR-S1113, Strasbourg, France
- Laboratoire d'Hématologie, Pôle de Biologie, Hôpital de Hautepierre, Hôpitaux Universitaires de Strasbourg, Strasbourg, France
| | - Laurent Mauvieux
- Université de Strasbourg, INSERM, IRFAC UMR-S1113, Strasbourg, France
- Laboratoire d'Hématologie, Pôle de Biologie, Hôpital de Hautepierre, Hôpitaux Universitaires de Strasbourg, Strasbourg, France
| | - Raoul Herbrecht
- Université de Strasbourg, INSERM, IRFAC UMR-S1113, Strasbourg, France
- Service d'Hématologie, Institut de Cancérologie Strasbourg Europe (ICANS), Strasbourg, France
| | - Sarah Cianferani
- Laboratoire de Spectrométrie de Masse BioOrganique, Université de Strasbourg, CNRS, IPHC, UMR 7178, Strasbourg, France
| | - Jean-Noel Freund
- Université de Strasbourg, INSERM, IRFAC UMR-S1113, Strasbourg, France
| | - Christine Carapito
- Laboratoire de Spectrométrie de Masse BioOrganique, Université de Strasbourg, CNRS, IPHC, UMR 7178, Strasbourg, France
| | - Myriam Maumy-Bertrand
- Fédération Hospitalo-Universitaire (FHU) Omicare, Université de Strasbourg, Strasbourg, France
- Institut de Recherche Mathématique Avancée, CNRS UMR 7501, LabEx IRMIA, Université de Strasbourg, Strasbourg, France
| | - Seiamak Bahram
- Laboratoire d'ImmunoRhumatologie Moléculaire, INSERM UMR-S1109, LabEx Transplantex, Plateforme Genomax, Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg, Strasbourg, France
- Fédération Hospitalo-Universitaire (FHU) Omicare, Université de Strasbourg, Strasbourg, France
- Laboratoire d'Immunologie, Plateau Technique de Biologie, Pôle de Biologie, Nouvel Hôpital Civil, Strasbourg, France
| | - Frederic Bertrand
- Institut de Recherche Mathématique Avancée, CNRS UMR 7501, LabEx IRMIA, Université de Strasbourg, Strasbourg, France.
- Fédération Hospitalo-Universitaire (FHU) Omicare, Université de Strasbourg, Strasbourg, France.
- Institut Charles Delaunay, ROSAS, M2S, Université de Technologie de Troyes, Troyes, France.
| | - Laurent Vallat
- Laboratoire d'ImmunoRhumatologie Moléculaire, INSERM UMR-S1109, LabEx Transplantex, Plateforme Genomax, Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg, Strasbourg, France.
- Fédération Hospitalo-Universitaire (FHU) Omicare, Université de Strasbourg, Strasbourg, France.
- Laboratoire d'Immunologie, Plateau Technique de Biologie, Pôle de Biologie, Nouvel Hôpital Civil, Strasbourg, France.
- Université de Strasbourg, INSERM, IRFAC UMR-S1113, Strasbourg, France.
- Laboratoire d'Hématologie, Pôle de Biologie, Hôpital de Hautepierre, Hôpitaux Universitaires de Strasbourg, Strasbourg, France.
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Mustachio LM, Chelariu-Raicu A, Szekvolgyi L, Roszik J. Targeting KRAS in Cancer: Promising Therapeutic Strategies. Cancers (Basel) 2021; 13:1204. [PMID: 33801965 PMCID: PMC7999304 DOI: 10.3390/cancers13061204] [Citation(s) in RCA: 50] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2021] [Accepted: 03/05/2021] [Indexed: 12/17/2022] Open
Abstract
The Kirsten rat sarcoma viral oncogene homolog (KRAS) is mutated in approximately 25% of all human cancers and is known to be a major player promoting and maintaining tumorigenesis through the RAS/MAPK pathway. Over the years, a large number of studies have identified strategies at different regulatory levels to tackle this 'difficult-to-target' oncoprotein. Yet, the most ideal strategy to overcome KRAS and its downstream effects has yet to be uncovered. This review summarizes the role of KRAS activating mutations in multiple cancer types as well as the key findings for potential strategies inhibiting its oncogenic behavior. A comprehensive analysis of the different pathways and mechanisms associated with KRAS activity in tumors will ultimately pave the way for promising future work that will identify optimum therapeutic strategies.
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Affiliation(s)
- Lisa Maria Mustachio
- Department of Epigenetics and Molecular Carcinogenesis, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
- Center for Cancer Epigenetics, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Anca Chelariu-Raicu
- Department of Obstetrics and Gynecology, University Hospital, Ludwig Maximilian University of Munich, 80539 Munich, Germany;
| | - Lorant Szekvolgyi
- Genome Architecture and Recombination Research Group, Department of Biochemistry and Molecular Biology, MTA-DE Momentum, Faculty of Medicine, University of Debrecen, 4002 Debrecen, Hungary;
| | - Jason Roszik
- Department of Genomic Medicine, Division of Cancer Medicine, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
- Department of Melanoma Medical Oncology, Division of Cancer Medicine, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
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49
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Wu Z, Zhao W, Yang Z, Wang YM, Dai Y, Chen LA. Novel Resistance Mechanisms to Osimertinib Analysed by Whole-Exome Sequencing in Non-Small Cell Lung Cancer. Cancer Manag Res 2021; 13:2025-2032. [PMID: 33658860 PMCID: PMC7920504 DOI: 10.2147/cmar.s292342] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2020] [Accepted: 01/31/2021] [Indexed: 12/25/2022] Open
Abstract
Purpose Molecular-based targeted therapy has improved life expectancy for advanced non-small cell lung cancer (NSCLC). However, it does not have to be inevitable that patients receiving third-generation EGFR-TKIs become drug resistant. EGFR C797S and MET amplification are common mechanisms of osimertinib. However, a large part of these potential drug mechanisms remains unknown, and further research is needed. Methods Tumour and blood samples from forty advanced NSCLC patients were identified as acquired drug resistant to osimertinib. The NGS panel was applied to detect EGFR C797S and MET amplification in tumour tissues or plasma samples. Whole-exome sequencing was conducted in five pairs of tumour tissues obtained before osimertinib administration and after osimertinib resistance in patients without C797S/cMET amplification. Results The overall C797S mutation rate was 20%, and MET amplification was detected in six out of sixteen C797S-negative samples. PDGFRA in the PI3K-AKT-mTOR signalling pathway, RASAL2, RIN3 and SOS2 in the RAS-Raf-ERK signalling pathway, PTK2 in the ERBB signalling pathway and ABCC1 and ABCB5 in the ABC membrane pump system were identified as candidate crucial genes of drug resistance to osimertinib. Conclusion EGFR C797S mutation and MET amplification are leading mechanisms for osimertinib resistance in lung cancer. The crucial potential mutated genes defined in our present study may need further validation in a considerable number of lung cancer patients.
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Affiliation(s)
- Zhen Wu
- Respiratory Department of Chinese PLA General Hospital, Beijing, People's Republic of China
| | - Wei Zhao
- Respiratory Department of Chinese PLA General Hospital, Beijing, People's Republic of China
| | - Zhen Yang
- Respiratory Department of Chinese PLA General Hospital, Beijing, People's Republic of China
| | - Yue Ming Wang
- School of Medicine, Nankai University, Tianjin, People's Republic of China
| | - Yu Dai
- Respiratory Department of Chinese PLA General Hospital, Beijing, People's Republic of China
| | - Liang-An Chen
- Respiratory Department of Chinese PLA General Hospital, Beijing, People's Republic of China.,School of Medicine, Nankai University, Tianjin, People's Republic of China
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50
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Future Approaches for Treating Chronic Myeloid Leukemia: CRISPR Therapy. BIOLOGY 2021; 10:biology10020118. [PMID: 33557401 PMCID: PMC7915349 DOI: 10.3390/biology10020118] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/11/2021] [Revised: 01/27/2021] [Accepted: 02/02/2021] [Indexed: 12/11/2022]
Abstract
Simple Summary In the last two decades, the therapeutic landscape of several tumors have changed profoundly with the introduction of drugs against proteins encoded by oncogenes. Oncogenes play an essential role in human cancer and when their encoded proteins are inhibited by specific drugs, the tumoral process can be reverted or stopped. An example of this is the case of the chronic myeloid leukemia, in which all the pathological features can be attributed by a single oncogene. Most patients with this disease now have a normal life expectancy thanks to a rationality designed inhibitor. However, the drug only blocks the protein, the oncogene continues unaffected and treatment discontinuation is only an option for a small subset of patients. With the advent of genome-editing nucleases and, especially, the CRISPR/Cas9 system, the possibilities to destroy oncogenes now is feasible. A novel therapeutic tool has been developed with unimaginable limits in cancer treatment. Recent studies support that CRISPR/Cas9 system could be a definitive therapeutic option in chronic myeloid leukemia. This work reviews the biology of chronic myeloid leukemia, the emergence of the CRISPR system, and its ability as a specific tool for this disease. Abstract The constitutively active tyrosine-kinase BCR/ABL1 oncogene plays a key role in human chronic myeloid leukemia development and disease maintenance, and determines most of the features of this leukemia. For this reason, tyrosine-kinase inhibitors are the first-line treatment, offering most patients a life expectancy like that of an equivalent healthy person. However, since the oncogene stays intact, lifelong oral medication is essential, even though this triggers adverse effects in many patients. Furthermore, leukemic stem cells remain quiescent and resistance is observed in approximately 25% of patients. Thus, new therapeutic alternatives are still needed. In this scenario, the interruption/deletion of the oncogenic sequence might be an effective therapeutic option. The emergence of CRISPR (clustered regularly interspaced short palindromic repeats) technology can offer a definitive treatment based on its capacity to induce a specific DNA double strand break. Besides, it has the advantage of providing complete and permanent oncogene knockout, while tyrosine kinase inhibitors (TKIs) only ensure that BCR-ABL1 oncoprotein is inactivated during treatment. CRISPR/Cas9 cuts DNA in a sequence-specific manner making it possible to turn oncogenes off in a way that was not previously feasible in humans. This review describes chronic myeloid leukemia (CML) disease and the main advances in the genome-editing field by which it may be treated in the future.
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