|
1
|
Fernandes P, Waldron N, Chatzilygeroudi T, Naji NS, Karantanos T. Acute Erythroid Leukemia: From Molecular Biology to Clinical Outcomes. Int J Mol Sci 2024; 25:6256. [PMID: 38892446 PMCID: PMC11172574 DOI: 10.3390/ijms25116256] [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: 04/12/2024] [Revised: 05/30/2024] [Accepted: 06/03/2024] [Indexed: 06/21/2024] Open
Abstract
Acute Erythroid Leukemia (AEL) is a rare and aggressive subtype of Acute Myeloid Leukemia (AML). In 2022, the World Health Organization (WHO) defined AEL as a biopsy with ≥30% proerythroblasts and erythroid precursors that account for ≥80% of cellularity. The International Consensus Classification refers to this neoplasm as "AML with mutated TP53". Classification entails ≥20% blasts in blood or bone marrow biopsy and a somatic TP53 mutation (VAF > 10%). This type of leukemia is typically associated with biallelic TP53 mutations and a complex karyotype, specifically 5q and 7q deletions. Transgenic mouse models have implicated several molecules in the pathogenesis of AEL, including transcriptional master regulator GATA1 (involved in erythroid differentiation), master oncogenes, and CDX4. Recent studies have also characterized AEL by epigenetic regulator mutations and transcriptome subgroups. AEL patients have overall poor clinical outcomes, mostly related to their poor response to the standard therapies, which include hypomethylating agents and intensive chemotherapy. Allogeneic bone marrow transplantation (AlloBMT) is the only potentially curative approach but requires deep remission, which is very challenging for these patients. Age, AlloBMT, and a history of antecedent myeloid neoplasms further affect the outcomes of these patients. In this review, we will summarize the diagnostic criteria of AEL, review the current insights into the biology of AEL, and describe the treatment options and outcomes of patients with this disease.
Collapse
Affiliation(s)
- Priyanka Fernandes
- Johns Hopkins School of Medicine, Baltimore, MD 21205, USA; (P.F.); (N.W.)
| | - Natalie Waldron
- Johns Hopkins School of Medicine, Baltimore, MD 21205, USA; (P.F.); (N.W.)
| | - Theodora Chatzilygeroudi
- Department of Oncology, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA; (T.C.); (N.S.N.)
| | - Nour Sabiha Naji
- Department of Oncology, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA; (T.C.); (N.S.N.)
| | - Theodoros Karantanos
- Johns Hopkins School of Medicine, Baltimore, MD 21205, USA; (P.F.); (N.W.)
- Department of Oncology, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA; (T.C.); (N.S.N.)
| |
Collapse
|
|
2
|
Fagnan A, Aid Z, Baille M, Drakul A, Robert E, Lopez CK, Thirant C, Lecluse Y, Rivière J, Ignacimouttou C, Salmoiraghi S, Anguita E, Naimo A, Marzac C, Pflumio F, Malinge S, Wichmann C, Huang Y, Lobry C, Chaumeil J, Soler E, Bourquin J, Nerlov C, Bernard OA, Schwaller J, Mercher T. The ETO2 transcriptional cofactor maintains acute leukemia by driving a MYB/EP300-dependent stemness program. Hemasphere 2024; 8:e90. [PMID: 38903535 PMCID: PMC11187848 DOI: 10.1002/hem3.90] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2024] [Revised: 04/13/2024] [Accepted: 05/01/2024] [Indexed: 06/22/2024] Open
Abstract
Transcriptional cofactors of the ETO family are recurrent fusion partners in acute leukemia. We characterized the ETO2 regulome by integrating transcriptomic and chromatin binding analyses in human erythroleukemia xenografts and controlled ETO2 depletion models. We demonstrate that beyond its well-established repressive activity, ETO2 directly activates transcription of MYB, among other genes. The ETO2-activated signature is associated with a poorer prognosis in erythroleukemia but also in other acute myeloid and lymphoid leukemia subtypes. Mechanistically, ETO2 colocalizes with EP300 and MYB at enhancers supporting the existence of an ETO2/MYB feedforward transcription activation loop (e.g., on MYB itself). Both small-molecule and PROTAC-mediated inhibition of EP300 acetyltransferases strongly reduced ETO2 protein, chromatin binding, and ETO2-activated transcripts. Taken together, our data show that ETO2 positively enforces a leukemia maintenance program that is mediated in part by the MYB transcription factor and that relies on acetyltransferase cofactors to stabilize ETO2 scaffolding activity.
Collapse
Affiliation(s)
- Alexandre Fagnan
- Gustave Roussy, INSERM U1170Université Paris‐SaclayVillejuifFrance
- Equipe Labellisée Ligue Contre le CancerParisFrance
- MRC Molecular Hematology Unit, MRC Weatherall Institute of Molecular Medicine, John Radcliffe HospitalUniversity of OxfordOxfordUK
| | - Zakia Aid
- Gustave Roussy, INSERM U1170Université Paris‐SaclayVillejuifFrance
- Equipe Labellisée Ligue Contre le CancerParisFrance
| | - Marie Baille
- Gustave Roussy, INSERM U1170Université Paris‐SaclayVillejuifFrance
- Equipe Labellisée Ligue Contre le CancerParisFrance
| | - Aneta Drakul
- Division of Oncology and Children's Research CentreUniversity Children's Hospital ZurichZurichSwitzerland
| | - Elie Robert
- Gustave Roussy, INSERM U1170Université Paris‐SaclayVillejuifFrance
- Equipe Labellisée Ligue Contre le CancerParisFrance
| | - Cécile K. Lopez
- Gustave Roussy, INSERM U1170Université Paris‐SaclayVillejuifFrance
- Equipe Labellisée Ligue Contre le CancerParisFrance
| | - Cécile Thirant
- Gustave Roussy, INSERM U1170Université Paris‐SaclayVillejuifFrance
- Equipe Labellisée Ligue Contre le CancerParisFrance
| | - Yann Lecluse
- Gustave Roussy, Plateforme Imagerie et Cytométrie, Université Paris‐Saclay, UMS AMMICA, INSERM US23, CNRS UMS 3655VillejuifFrance
| | - Julie Rivière
- Gustave Roussy, INSERM U1170Université Paris‐SaclayVillejuifFrance
- Equipe Labellisée Ligue Contre le CancerParisFrance
| | - Cathy Ignacimouttou
- Gustave Roussy, INSERM U1170Université Paris‐SaclayVillejuifFrance
- Equipe Labellisée Ligue Contre le CancerParisFrance
| | - Silvia Salmoiraghi
- Department of Oncology and HematologyAzienda Socio Sanitaria Territoriale Papa Giovanni XXIII, FROM Research Foundation, Papa Giovanni XXIII HospitalBergamoItaly
| | - Eduardo Anguita
- Hematology Department, Hospital Clínico San Carlos (HCSC), IML, IdISSC, Department of MedicineUniversidad Complutense de Madrid (UCM)MadridSpain
| | - Audrey Naimo
- Gustave Roussy, Genomic PlatformUniversité Paris‐Saclay, UMS AMMICA, INSERM US23, CNRS UMS 3655VillejuifFrance
| | - Christophe Marzac
- Department of HematologyLeukemia Interception Program, Personalized Cancer Prevention Center, Gustave RoussyVillejuifFrance
| | - Françoise Pflumio
- Equipe Labellisée Ligue Contre le CancerParisFrance
- Unité de Recherche (UMR)‐E008 Stabilité Génétique, Cellules Souches et Radiations, Team Niche and Cancer in Hematopoiesis, Commissariat à l'Energie Atomique et aux Energies Alternatives (CEA)Université de Paris‐Université Paris‐SaclayFontenay‐aux‐RosesFrance
- OPALE Carnot Institute, The Organization for Partnerships in LeukemiaParisFrance
| | - Sébastien Malinge
- Gustave Roussy, INSERM U1170Université Paris‐SaclayVillejuifFrance
- Telethon Kids Institute, Perth Children's HospitalNedlandsAustralia
| | - Christian Wichmann
- Department of Transfusion Medicine, Cell Therapeutics and HaemostasisLudwig‐Maximilians‐University of MunichMunichGermany
| | - Yun Huang
- Division of Oncology and Children's Research CentreUniversity Children's Hospital ZurichZurichSwitzerland
| | - Camille Lobry
- Gustave Roussy, INSERM U1170Université Paris‐SaclayVillejuifFrance
- INSERM U944, CNRS UMR7212Institut de Recherche Saint Louis and Université de ParisParisFrance
| | - Julie Chaumeil
- Université de Paris, Institut Cochin, INSERM, CNRSParisFrance
| | - Eric Soler
- IGMM, University of Montpellier, CNRS, Montpellier, France & Université de Paris, Laboratory of Excellence GR‐ExParisFrance
| | - Jean‐Pierre Bourquin
- Division of Oncology and Children's Research CentreUniversity Children's Hospital ZurichZurichSwitzerland
| | - Claus Nerlov
- MRC Molecular Hematology Unit, MRC Weatherall Institute of Molecular Medicine, John Radcliffe HospitalUniversity of OxfordOxfordUK
| | | | - Juerg Schwaller
- Department of BiomedicineUniversity Children's Hospital Beider Basel (UKBB), University of BaselBaselSwitzerland
| | - Thomas Mercher
- Gustave Roussy, INSERM U1170Université Paris‐SaclayVillejuifFrance
- Equipe Labellisée Ligue Contre le CancerParisFrance
- OPALE Carnot Institute, The Organization for Partnerships in LeukemiaParisFrance
| |
Collapse
|
|
3
|
Abdoul-Azize S, Hami R, Riou G, Derambure C, Charbonnier C, Vannier JP, Guzman ML, Schneider P, Boyer O. Glucocorticoids paradoxically promote steroid resistance in B cell acute lymphoblastic leukemia through CXCR4/PLC signaling. Nat Commun 2024; 15:4557. [PMID: 38811530 PMCID: PMC11136999 DOI: 10.1038/s41467-024-48818-9] [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: 02/15/2023] [Accepted: 05/15/2024] [Indexed: 05/31/2024] Open
Abstract
Glucocorticoid (GC) resistance in childhood relapsed B-cell acute lymphoblastic leukemia (B-ALL) represents an important challenge. Despite decades of clinical use, the mechanisms underlying resistance remain poorly understood. Here, we report that in B-ALL, GC paradoxically induce their own resistance by activating a phospholipase C (PLC)-mediated cell survival pathway through the chemokine receptor, CXCR4. We identify PLC as aberrantly activated in GC-resistant B-ALL and its inhibition is able to induce cell death by compromising several transcriptional programs. Mechanistically, dexamethasone (Dex) provokes CXCR4 signaling, resulting in the activation of PLC-dependent Ca2+ and protein kinase C signaling pathways, which curtail anticancer activity. Treatment with a CXCR4 antagonist or a PLC inhibitor improves survival of Dex-treated NSG mice in vivo. CXCR4/PLC axis inhibition significantly reverses Dex resistance in B-ALL cell lines (in vitro and in vivo) and cells from Dex resistant ALL patients. Our study identifies how activation of the PLC signalosome in B-ALL by Dex limits the upfront efficacy of this chemotherapeutic agent.
Collapse
Affiliation(s)
| | - Rihab Hami
- Univ Brest, Inserm, UMR 1101, F-29200, Brest, France
| | - Gaetan Riou
- Univ Rouen Normandie, Inserm, UMR 1234, F-76000, Rouen, France
| | | | | | | | - Monica L Guzman
- Division of Hematology and Oncology, Department of Medicine, Weill Cornell Medicine, New York, NY, USA
| | - Pascale Schneider
- Univ Rouen Normandie, Inserm, UMR 1234, F-76000, Rouen, France
- Rouen University Hospital, Department of Pediatric Immuno-Hemato-Oncology, F-76000, Rouen, France
| | - Olivier Boyer
- Univ Rouen Normandie, Inserm, UMR 1234, F-76000, Rouen, France
- Rouen University Hospital, Department of Immunology and Biotherapy, F-76000, Rouen, France
| |
Collapse
|
|
4
|
Xiang Y, Liu X, Sun Q, Liao K, Liu X, Zhao Z, Feng L, Liu Y, Wang B. The development of cancers research based on mitochondrial heat shock protein 90. Front Oncol 2023; 13:1296456. [PMID: 38098505 PMCID: PMC10720920 DOI: 10.3389/fonc.2023.1296456] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2023] [Accepted: 11/23/2023] [Indexed: 12/17/2023] Open
Abstract
Mitochondrial heat shock protein 90 (mtHsp90), including Tumor necrosis factor receptor-associated protein 1 (TRAP1) and Hsp90 translocated from cytoplasm, modulating cellular metabolism and signaling pathways by altering the conformation, activity, and stability of numerous client proteins, and is highly expressed in tumors. mtHsp90 inhibition results in the destabilization and eventual degradation of its client proteins, leading to interference with various tumor-related pathways and efficient control of cancer cell development. Among these compounds, gamitrinib, a specific mtHsp90 inhibitor, has demonstrated its safety and efficacy in several preclinical investigations and is currently undergoing evaluation in clinical trials. This review aims to provide a comprehensive overview of the present knowledge pertaining to mtHsp90, encompassing its structure and function. Moreover, our main emphasis is on the development of mtHsp90 inhibitors for various cancer therapies, to present a thorough overview of the recent pre-clinical and clinical advancements in this field.
Collapse
Affiliation(s)
- Yuchu Xiang
- West China Hospital of Sichuan University, Sichuan University, Chengdu, China
| | - Xudong Liu
- Institute of Medical Microbiology and Hygiene, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Qi Sun
- Department of Pharmacology and Pharmacy, Li Ka Shing Faculty of Medicine, Centre for Safe Medication Practice and Research, The University of Hong Kong, Pok Fu Lam, Hong Kong SAR, China
| | - Kuo Liao
- School of Biology and Biological Engineering, South China University of Technology, Guangzhou, China
| | - Xiaohan Liu
- Multiscale Research Institute of Complex Systems, Fudan University, Shanghai, China
| | - Zihui Zhao
- Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Lishuang Feng
- School of Public Health, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, Hong Kong SAR, China
| | - Yan Liu
- Department of Organ Transplantation, Guizhou Provincial People’s Hospital, Guiyang, Guizhou, China
| | - Bo Wang
- Institute of Medical Microbiology and Hygiene, Faculty of Medicine, University of Freiburg, Freiburg, Germany
- Department of Urology, Guizhou Provincial People’s Hospital, Guiyang, Guizhou, China
| |
Collapse
|
|
5
|
Ma Z, Ye W, Huang X, Li X, Li F, Lin X, Hu C, Wang J, Jin J, Zhu B, Huang J. The ferroptosis landscape in acute myeloid leukemia. Aging (Albany NY) 2023; 15:13486-13503. [PMID: 38032290 DOI: 10.18632/aging.205257] [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: 06/02/2021] [Accepted: 10/17/2023] [Indexed: 12/01/2023]
Abstract
Ferroptosis induction through the suppression of glutathione peroxidase 4 (GPX4) and apoptosis-inducing factor mitochondria-associated 2 (AIFM2) has proven to be an effective approach in eliminating chemotherapy-resistant cells of various types. However, a comprehensive understanding of the roles of GPX4 and AIFM2 in acute myeloid leukemia (AML) has not yet been achieved. Using cBioPortal, DepMap, GEPIA, Metascape, and ONCOMINE, we compared the transcriptional expression, survival data, gene mutation, methylation, and network analyses of GPX4- and AIFM2-associated signaling pathways in AML. The results revealed that high expression levels of GPX4 and AIFM2 are associated with an adverse prognosis for AML patients. Overexpression of AIFM2 correlated with elevated mutation frequencies in NPM1 and DNMT3A. GPX4 upregulation modulated the following pathways: GO:0045333, cellular respiration; R-HSA-5389840, mitochondrial translation elongation; GO:0009060, aerobic respiration; R-HSA-9609507, protein localization; and R-HSA-8953854, metabolism of RNA. On the other hand, the overexpression of AIFM2 influenced the following processes: GO:0048704, embryonic skeletal system morphogenesis; GO:0021546, rhombomere development; GO:0009954, proximal/distal pattern formation; and GO:0048732, gland development. This study identifies the high expression of GPX4 and AIFM2 as novel biomarkers predicting a poor prognosis for AML patients. Furthermore, ferroptosis induction may improve the stratified treatment of AML.
Collapse
Affiliation(s)
- Zhixin Ma
- Clinical Prenatal Diagnosis Center, Key Laboratory of Reproductive Genetics, Women's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Wenle Ye
- Department of Hematology, Key Laboratory of Hematologic Malignancies, Diagnosis and Treatment, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Xin Huang
- Department of Hematology, Key Laboratory of Hematologic Malignancies, Diagnosis and Treatment, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Xia Li
- Department of Hematology, Key Laboratory of Hematologic Malignancies, Diagnosis and Treatment, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Fenglin Li
- Department of Hematology, Key Laboratory of Hematologic Malignancies, Diagnosis and Treatment, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Xiangjie Lin
- Department of Hematology, Key Laboratory of Hematologic Malignancies, Diagnosis and Treatment, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Chao Hu
- Department of Hematology, Key Laboratory of Hematologic Malignancies, Diagnosis and Treatment, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Jinghan Wang
- Department of Hematology, Key Laboratory of Hematologic Malignancies, Diagnosis and Treatment, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Jie Jin
- Department of Hematology, Key Laboratory of Hematologic Malignancies, Diagnosis and Treatment, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Bo Zhu
- Clinical Prenatal Diagnosis Center, Key Laboratory of Reproductive Genetics, Women's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Jiansong Huang
- Department of Hematology, Key Laboratory of Hematologic Malignancies, Diagnosis and Treatment, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| |
Collapse
|
|
6
|
Han N, Yuan M, Yan L, Tang H. Emerging Insights into Liver X Receptor α in the Tumorigenesis and Therapeutics of Human Cancers. Biomolecules 2023; 13:1184. [PMID: 37627249 PMCID: PMC10452869 DOI: 10.3390/biom13081184] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2023] [Revised: 07/24/2023] [Accepted: 07/26/2023] [Indexed: 08/27/2023] Open
Abstract
Liver X receptor α (LXRα), a member of the nuclear receptor superfamily, is identified as a protein activated by ligands that interacts with the promoters of specific genes. It regulates cholesterol, bile acid, and lipid metabolism in normal physiological processes, and it participates in the development of some related diseases. However, many studies have demonstrated that LXRα is also involved in regulating numerous human malignancies. Aberrant LXRα expression is emerging as a fundamental and pivotal factor in cancer cell proliferation, invasion, apoptosis, and metastasis. Herein, we outline the expression levels of LXRα between tumor tissues and normal tissues via the Oncomine and Tumor Immune Estimation Resource (TIMER) 2.0 databases; summarize emerging insights into the roles of LXRα in the development, progression, and treatment of different human cancers and their diversified mechanisms; and highlight that LXRα can be a biomarker and therapeutic target in diverse cancers.
Collapse
Affiliation(s)
- Ning Han
- Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu 610041, China
- Division of Infectious Diseases, State Key Laboratory of Biotherapy, Sichuan University, Chengdu 610041, China
| | - Man Yuan
- Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu 610041, China
| | - Libo Yan
- Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu 610041, China
- Division of Infectious Diseases, State Key Laboratory of Biotherapy, Sichuan University, Chengdu 610041, China
| | - Hong Tang
- Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu 610041, China
- Division of Infectious Diseases, State Key Laboratory of Biotherapy, Sichuan University, Chengdu 610041, China
| |
Collapse
|
|
7
|
Li H, Zhang D, Fu Q, Wang S, Zhang X, Lin Z, Wang Z, Song J, Su Z, Xue V, Liu S, Chen Y, Zhou L, Zhao N, Lu D. WDR54 exerts oncogenic roles in T-cell acute lymphoblastic leukemia. Cancer Sci 2023. [PMID: 37302808 PMCID: PMC10394158 DOI: 10.1111/cas.15872] [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: 01/07/2023] [Revised: 05/07/2023] [Accepted: 05/17/2023] [Indexed: 06/13/2023] Open
Abstract
WDR54 has been recently identified as a novel oncogene in colorectal and bladder cancers. However, the expression and function of WDR54 in T-cell acute lymphoblastic leukemia (T-ALL) were not reported. In this study, we investigated the expression of WDR54 in T-ALL, as well as its function in T-ALL pathogenesis using cell lines and T-ALL xenograft. Bioinformatics analysis indicated high mRNA expression of WDR54 in T-ALL. We further confirmed that the expression of WDR54 was significantly elevated in T-ALL. Depletion of WDR54 dramatically inhibited cell viability and induced apoptosis and cell cycle arrest at S phase in T-ALL cells in vitro. Moreover, knockdown of WDR54 impeded the process of leukemogenesis in a Jurkat xenograft model in vivo. Mechanistically, the expression of PDPK1, phospho-AKT (p-AKT), total AKT, phospho-ERK (p-ERK), Bcl-2 and Bcl-xL were downregulated, while cleaved caspase-3 and cleaved caspase-9 were upregulated in T-ALL cells with WDR54 knockdown. Additionally, RNA-seq analysis indicated that WDR54 might regulate the expression of some oncogenic genes involved in multiple signaling pathways. Taken together, these findings suggest that WDR54 may be involved in the pathogenesis of T-ALL and serve as a potential therapeutic target for the treatment of T-ALL.
Collapse
Affiliation(s)
- Huan Li
- Guangdong Provincial Key Laboratory of Regional Immunity and Diseases, International Cancer Center, Marshall Laboratory of Biomedical Engineering, Department of Pharmacology, Shenzhen University Medical School, Shenzhen, China
| | - Danlan Zhang
- Guangdong Provincial Key Laboratory of Regional Immunity and Diseases, International Cancer Center, Marshall Laboratory of Biomedical Engineering, Department of Pharmacology, Shenzhen University Medical School, Shenzhen, China
| | - Qiuxia Fu
- Guangdong Provincial Key Laboratory of Regional Immunity and Diseases, International Cancer Center, Marshall Laboratory of Biomedical Engineering, Department of Pharmacology, Shenzhen University Medical School, Shenzhen, China
| | - Shang Wang
- Chongqing Key Laboratory of Traditional Chinese Medicine for Prevention and Cure of Metabolic Diseases, College of Traditional Chinese Medicine, Chongqing Medical University, Chongqing, China
| | - Xin Zhang
- Guangdong Provincial Key Laboratory of Regional Immunity and Diseases, International Cancer Center, Marshall Laboratory of Biomedical Engineering, Department of Pharmacology, Shenzhen University Medical School, Shenzhen, China
| | - Zhixian Lin
- Guangdong Provincial Key Laboratory of Regional Immunity and Diseases, International Cancer Center, Marshall Laboratory of Biomedical Engineering, Department of Pharmacology, Shenzhen University Medical School, Shenzhen, China
| | - Zhongyuan Wang
- Guangdong Provincial Key Laboratory of Regional Immunity and Diseases, International Cancer Center, Marshall Laboratory of Biomedical Engineering, Department of Pharmacology, Shenzhen University Medical School, Shenzhen, China
| | - Jiaxing Song
- Guangdong Provincial Key Laboratory of Regional Immunity and Diseases, International Cancer Center, Marshall Laboratory of Biomedical Engineering, Department of Pharmacology, Shenzhen University Medical School, Shenzhen, China
| | - Zijie Su
- Guangdong Provincial Key Laboratory of Regional Immunity and Diseases, International Cancer Center, Marshall Laboratory of Biomedical Engineering, Department of Pharmacology, Shenzhen University Medical School, Shenzhen, China
| | - VivianWeiwen Xue
- Guangdong Provincial Key Laboratory of Regional Immunity and Diseases, International Cancer Center, Marshall Laboratory of Biomedical Engineering, Department of Pharmacology, Shenzhen University Medical School, Shenzhen, China
| | - Shanshan Liu
- Guangdong Provincial Key Laboratory of Regional Immunity and Diseases, International Cancer Center, Marshall Laboratory of Biomedical Engineering, Department of Pharmacology, Shenzhen University Medical School, Shenzhen, China
| | - Yun Chen
- Department of Immunology, Key Laboratory of Human Functional Genomics of Jiangsu Province, Gusu School, Nanjing Medical University, Nanjing, China
| | - Liang Zhou
- Guangdong Provincial Key Laboratory of Regional Immunity and Diseases, International Cancer Center, Marshall Laboratory of Biomedical Engineering, Department of Pharmacology, Shenzhen University Medical School, Shenzhen, China
| | - Na Zhao
- Department of Hematology, the First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - Desheng Lu
- Guangdong Provincial Key Laboratory of Regional Immunity and Diseases, International Cancer Center, Marshall Laboratory of Biomedical Engineering, Department of Pharmacology, Shenzhen University Medical School, Shenzhen, China
| |
Collapse
|
|
8
|
Karapanagioti A, Nasiri-Ansari N, Moustogiannis A, Trigas GC, Zografos G, Aggeli C, Kyriakopoulos G, Choreftaki T, Philippou A, Kaltsas G, Kassi E, Angelousi A. What is the role of CHCHD2 in adrenal tumourigenesis? Endocrine 2023:10.1007/s12020-023-03393-9. [PMID: 37221428 DOI: 10.1007/s12020-023-03393-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/21/2022] [Accepted: 05/01/2023] [Indexed: 05/25/2023]
Abstract
PURPOSE CHCHD2 is an antiapoptotic mitochondrial protein acting through the BCL2/BAX pathway in various cancers. However, data on the regulatory role of CHCHD2 in adrenal tumourigenesis are scarce. METHODS We studied the expression of CHCHD2, BCL2, and BAX in human adrenocortical tissues and SW13 cells. mRNA and protein levels were analyzed through qPCR and immunoblotting, respectively, in 16 benign adrenocortical neoplasms (BANs), along with their adjacent normal adrenal tissues (controls), and 10 adrenocortical carcinomas (ACCs). BCL2/BAX mRNA expression was also analyzed in SW13 cells after CHCHD2 silencing. MTS, flow cytometry and scratch assays were performed to assess cell viability, apoptosis, and invasion, respectively. RESULTS BCL2 and CHCHCD2 mRNA and protein expression was increased in BANs compared to normal adrenal tissues whereas BAX was decreased. BAX and CHCHD2 mRNA and protein levels were significantly downregulated and upregulated, respectively, in ACCs compared with either BANs or controls. Expression of the studied genes was not different among cortisol-secreting and nonfunctional ACAs. No significant association was found between genes' expression and other established prognostic markers of ACCs patients. In vitro analysis showed that CHCHD2 silencing resulted in reduced cell viability and invasion as well as increased SW13 cells apoptosis. CONCLUSIONS CHCHD2 expression seems to be implicated in adrenal tumourigenesis and its absence resulted to increased apoptosis in vitro. However, the exact mechanism of action and particularly its association with the BAX/BCL2 pathway needs to be further studied and evaluate whether it could be a protentional therapeutic target.
Collapse
Affiliation(s)
- Angeliki Karapanagioti
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, Athens, Greece
- 1st Department of Propaedeutic Internal Medicine, Laikon University Hospital, National and Kapodistrian University of Athens, Athens, Greece
| | - Narjes Nasiri-Ansari
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Athanasios Moustogiannis
- Department of Experimental Physiology, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - George C Trigas
- Department of Histology and Embryology, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Georgios Zografos
- 3rd Department of Surgery, General Hospital of Athens "G. Gennimatas", Athens, Greece
| | - Chrysanthi Aggeli
- 3rd Department of Surgery, General Hospital of Athens "G. Gennimatas", Athens, Greece
| | | | - Theodosia Choreftaki
- Department of Pathology, General Hospital of Athens "G. Gennimatas", Athens, Greece
| | - Anastassios Philippou
- Department of Experimental Physiology, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Gregory Kaltsas
- 1st Department of Propaedeutic Internal Medicine, Laikon University Hospital, National and Kapodistrian University of Athens, Athens, Greece
| | - Eva Kassi
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, Athens, Greece
- 1st Department of Propaedeutic Internal Medicine, Laikon University Hospital, National and Kapodistrian University of Athens, Athens, Greece
| | - Anna Angelousi
- 1st Department of Internal Medicine, Laikon University Hospital, National and Kapodistrian University of Athens, Athens, Greece.
| |
Collapse
|
|
9
|
Wang YH, Yao CY, Lin CC, Gurashi K, Amaral FMR, Bossenbroek H, Jerez A, Somervaille TCP, Binder M, Patnaik MM, Hou HA, Chou WC, Batta K, Wiseman DH, Tien HF. A three-gene leukaemic stem cell signature score is robustly prognostic in chronic myelomonocytic leukaemia. Br J Haematol 2023; 201:302-307. [PMID: 36746431 DOI: 10.1111/bjh.18681] [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: 11/11/2022] [Revised: 01/09/2023] [Accepted: 01/20/2023] [Indexed: 02/08/2023]
Abstract
Leukaemic stem cell (LSC) gene expression has recently been linked to prognosis in patients with acute myeloid leukaemia (17-gene LSC score, LSC-17) and myelodysplastic syndromes. Although chronic myelomonocytic leukaemia (CMML) is regarded as a stem cell disorder, the clinical and biological impact of LSCs on CMML patients remains elusive. Making use of multiple independent validation cohorts, we here describe a concise three-gene expression signature (LSC-3, derived from the LSC-17 score) as an independent and robust prognostic factor for leukaemia-free and overall survival in CMML. We propose that LSC-3 could be used to supplement existing risk stratification systems, to improve prognostic performance and guide management decisions.
Collapse
Affiliation(s)
- Yu-Hung Wang
- Division of Cancer Sciences, The University of Manchester, Manchester, UK
- Division of Hematology, National Taiwan University Hospital, Taipei, Taiwan
- Leukaemia Biology Laboratory, Cancer Research UK Manchester Institute, Manchester, UK
| | - Chi-Yuan Yao
- Division of Hematology, National Taiwan University Hospital, Taipei, Taiwan
- Department of Laboratory Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - Chien-Chin Lin
- Division of Hematology, National Taiwan University Hospital, Taipei, Taiwan
- Department of Laboratory Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - Kristian Gurashi
- Division of Cancer Sciences, The University of Manchester, Manchester, UK
| | - Fabio M R Amaral
- Leukaemia Biology Laboratory, Cancer Research UK Manchester Institute, Manchester, UK
| | - Hasse Bossenbroek
- Division of Cancer Sciences, The University of Manchester, Manchester, UK
| | - Andres Jerez
- Haematology Department, Hospital Morales Meseguer, Murcia, Spain
| | - Tim C P Somervaille
- Leukaemia Biology Laboratory, Cancer Research UK Manchester Institute, Manchester, UK
| | - Moritz Binder
- Division of Hematology, Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota, USA
| | - Mrinal M Patnaik
- Division of Hematology, Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota, USA
| | - Hsin-An Hou
- Division of Hematology, National Taiwan University Hospital, Taipei, Taiwan
| | - Wen-Chien Chou
- Division of Hematology, National Taiwan University Hospital, Taipei, Taiwan
- Department of Laboratory Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - Kiran Batta
- Division of Cancer Sciences, The University of Manchester, Manchester, UK
| | - Daniel H Wiseman
- Division of Cancer Sciences, The University of Manchester, Manchester, UK
| | - Hwei-Fang Tien
- Division of Hematology, National Taiwan University Hospital, Taipei, Taiwan
- Department of Internal Medicine, Fra-Eastern Memorial Hospital, New Taipei City, Taiwan
| |
Collapse
|
|
10
|
Nabil R, Abdellateif MS, Gamal H, Hassan NM, Badawy RH, Ghareeb M, El Ashry MS. Clinical significance of EVI-1 gene expression and aberrations in patient with de-novo acute myeloid and acute lymphoid leukemia. Leuk Res 2023; 126:107019. [PMID: 36657369 DOI: 10.1016/j.leukres.2023.107019] [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: 11/17/2022] [Revised: 12/28/2022] [Accepted: 01/13/2023] [Indexed: 01/15/2023]
Abstract
BACKGROUND Acute leukemia is a common health problem in adults and children, however its exact molecular etiology is still unclear. METHODS The expression of EVI-1 was assessed in the bone marrow of 178 de-novo acute leukemia patients (101 AML, 71 ALL and 6 MPAL), compared to 40 control subjects. EVI-1 gene aberrations were also assessed in 69 AML patients using Fluorescence in situ hybridization (FISH) technique. RESULTS The expression of EVI-1 was significantly lower in ALL patients compared to control [0.177 (0.002-15.189) vs 0.953 (0.179-1.68); respectively, P = 0.009]. There was no significant difference between AML patients and control group [0.150 (0.0-641) vs 0.953 (0.179-1.68); respectively, P = 0.082]. The sensitivity, specificity, AUC of EVI-1 in ALL were (80.3 %, 60 % and 0.778; respectively, P = 0.009), and (67.3 %, 60 %, 0.667; respectively P = 0.082) in AML patients. One patient showed EVI-1 gene rearrangement in a complex karyotype and four patients showed EVI-1 amplification in hyperdiploid karyotypes. All patients with BCR-ABL fusion were EVI-1 over-expressers (P = 0.010). AML patients with EVI-1 low expression were positively associated with t(8;21)(q22;q22)RUNX1:RUNX1T1 fusion, favorable recurrent translocation, and low genetic risk (P = 0.037, P = 0.023, and P = 0.013; respectively). There was a significant association between low EVI-1 expression and prolonged overall survival (OS) in AML patients, while there was no significant association with the disease-free survival (DFS) (P = 0.048 and P = 0.419). There was no significant impact of EVI-1 expression on OS and DFS rates in ALL patients. CONCLUSION EVI-1 expression could be a helpful diagnostic, prognostic, and predictive biomarker for acute leukemia especially in AML.
Collapse
Affiliation(s)
- Reem Nabil
- Clinical Pathology Department, National Cancer Institute, Cairo University, Egypt
| | - Mona S Abdellateif
- Medical Biochemistry and Molecular Biology, Cancer Biology Department, National Cancer Institute, Cairo University, Egypt.
| | - Hend Gamal
- Clinical Pathology Department, National Cancer Institute, Cairo University, Egypt
| | - Naglaa M Hassan
- Clinical Pathology Department, National Cancer Institute, Cairo University, Egypt
| | - Ragia H Badawy
- Clinical Pathology Department, National Cancer Institute, Cairo University, Egypt
| | - Mohamed Ghareeb
- Medical Oncology Department, National Cancer Institute, Cairo University, Egypt
| | - Mona S El Ashry
- Clinical Pathology Department, National Cancer Institute, Cairo University, Egypt
| |
Collapse
|
|
11
|
Jung J, Gokhale S, Xie P. TRAF3: A novel regulator of mitochondrial physiology and metabolic pathways in B lymphocytes. Front Oncol 2023; 13:1081253. [PMID: 36776285 PMCID: PMC9911533 DOI: 10.3389/fonc.2023.1081253] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2022] [Accepted: 01/13/2023] [Indexed: 01/28/2023] Open
Abstract
Mitochondria, the organelle critical for cell survival and metabolism, are exploited by cancer cells and provide an important therapeutic target in cancers. Mitochondria dynamically undergo fission and fusion to maintain their diverse functions. Proteins controlling mitochondrial fission and fusion have been recognized as essential regulators of mitochondrial functions, mitochondrial quality control, and cell survival. In a recent proteomic study, we identified the key mitochondrial fission factor, MFF, as a new interacting protein of TRAF3, a known tumor suppressor of multiple myeloma and other B cell malignancies. This interaction recruits the majority of cytoplasmic TRAF3 to mitochondria, allowing TRAF3 to regulate mitochondrial morphology, mitochondrial functions, and mitochondria-dependent apoptosis in resting B lymphocytes. Interestingly, recent transcriptomic, metabolic and lipidomic studies have revealed that TRAF3 also vitally regulates multiple metabolic pathways in B cells, including phospholipid metabolism, glucose metabolism, and ribonucleotide metabolism. Thus, TRAF3 emerges as a novel regulator of mitochondrial physiology and metabolic pathways in B lymphocytes and B cell malignancies. Here we review current knowledge in this area and discuss relevant clinical implications.
Collapse
Affiliation(s)
- Jaeyong Jung
- Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, NJ, United States.,Graduate Program in Cellular and Molecular Pharmacology, Rutgers University, Piscataway, NJ, United States
| | - Samantha Gokhale
- Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, NJ, United States.,Graduate Program in Cellular and Molecular Pharmacology, Rutgers University, Piscataway, NJ, United States
| | - Ping Xie
- Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, NJ, United States.,Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, United States
| |
Collapse
|
|
12
|
Kang Y, Yang X, Feng Z, Lv R, Zhu J. Tumor-associated macrophages improve hypoxia-induced endoplasmic reticulum stress response in colorectal cancer cells by regulating TGF-β1/SOX4. Cell Signal 2022; 99:110430. [PMID: 35933032 DOI: 10.1016/j.cellsig.2022.110430] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2021] [Revised: 07/29/2022] [Accepted: 08/01/2022] [Indexed: 12/24/2022]
Abstract
Hypoxia is a common feature of solid tumors that can induce endoplasmic reticulum stress (ERS). This study aimed to explore the mechanism behind tumor-associated macrophages (TAMs) improving the ERS response of colorectal cancer (CRC) under hypoxic conditions. Herein, it was demonstrated that TAMs reduce ERS by secreting TGF-β1 and activating SOX4/TMEM2 signaling in CRC cells. The expression levels of TGF-β1, SOX4, and TMEM2 in 20 pairs of tumor tissues and para-carcinoma tissues were assessed. A co-culture system of CRC cells with THP-1-derived macrophages under hypoxic conditions in vitro was investigated to determine the protective effect of TAMs on CRC cells. Moreover, to further verify the underlying mechanism, TGF-β1 and SOX4 were knocked down in the TAMs and CRC cells, respectively. The results exposed that TGF-β1, SOX4, and TMEM2 were abundantly expressed in tumor tissues. Moreover, the co-culture system revealed that macrophages stimulate TGF-β1 secretion under hypoxia, which depresses the CRC cells' ERS, further promoting cell proliferation and inhibiting apoptosis. Furthermore, increased TGF-β1 levels promoted the expression of SOX4 and TMEM2 in CRC cells. Conversely, the knockdown of SOX4 attenuated the protective effect of TAMs on TGF-β1-stimulated CRC cells. In conclusion, these results suggest that the elevated ERS induced by hypoxia in CRC cells could be relieved by TAMs via the secretion of TGF-β1. Finally, TGF-β1 suppresses undue ERS response in CRC cells by activating the SOX4-TMEM2 axis.
Collapse
Affiliation(s)
- Yuqing Kang
- Department of Anesthesiology, Jinshan Branch Hospital of Shanghai Sixth People's Hospital, Shanghai, China
| | - Xuezhong Yang
- Department of Anesthesiology, Zhoupu Hospital of Pudong New Area, Shanghai, China
| | - Zhaoming Feng
- Department of Anesthesiology, Jinshan Branch Hospital of Shanghai Sixth People's Hospital, Shanghai, China
| | - Ranxu Lv
- Department of Anesthesiology, Jinshan Branch Hospital of Shanghai Sixth People's Hospital, Shanghai, China
| | - Junfeng Zhu
- Department of Anesthesiology, Jinshan Branch Hospital of Shanghai Sixth People's Hospital, Shanghai, China.
| |
Collapse
|
|
13
|
Comprehensive Landscape of STEAP Family Members Expression in Human Cancers: Unraveling the Potential Usefulness in Clinical Practice Using Integrated Bioinformatics Analysis. DATA 2022. [DOI: 10.3390/data7050064] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023] Open
Abstract
The human Six-Transmembrane Epithelial Antigen of the Prostate (STEAP) family comprises STEAP1-4. Several studies have pointed out STEAP proteins as putative biomarkers, as well as therapeutic targets in several types of human cancers, particularly in prostate cancer. However, the relationships and significance of the expression pattern of STEAP1-4 in cancer cases are barely known. Herein, the Oncomine database and cBioPortal platform were selected to predict the differential expression levels of STEAP members and clinical prognosis. The most common expression pattern observed was the combination of the over- and underexpression of distinct STEAP genes, but cervical and gastric cancer and lymphoma showed overexpression of all STEAP genes. It was also found that STEAP genes’ expression levels were already deregulated in benign lesions. Regarding the prognostic value, it was found that STEAP1 (prostate), STEAP2 (brain and central nervous system), STEAP3 (kidney, leukemia and testicular) and STEAP4 (bladder, cervical, gastric) overexpression correlate with lower patient survival rate. However, in prostate cancer, overexpression of the STEAP4 gene was correlated with a higher survival rate. Overall, this study first showed that the expression levels of STEAP genes are highly variable in human cancers, which may be related to different patients’ outcomes.
Collapse
|
|
14
|
Liu XS, Yang JW, Zeng J, Chen XQ, Gao Y, Kui XY, Liu XY, Zhang Y, Zhang YH, Pei ZJ. SLC2A1 is a Diagnostic Biomarker Involved in Immune Infiltration of Colorectal Cancer and Associated With m6A Modification and ceRNA. Front Cell Dev Biol 2022; 10:853596. [PMID: 35399515 PMCID: PMC8987357 DOI: 10.3389/fcell.2022.853596] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2022] [Accepted: 02/22/2022] [Indexed: 12/11/2022] Open
Abstract
Background: Overexpression of solute carrier family 2 member 1 (SLC2A1) promotes glycolysis and proliferation and migration of various tumors. However, there are few comprehensive studies on SLC2A1 in colorectal cancer (CRC).Methods: Oncomine, The Cancer Genome Atlas (TCGA), and Gene Expression Omnibus (GEO) databases were used to analyze the expression of SLC2A1 in pan-cancer and CRC and analyzed the correlation between SLC2A1 expression and clinical characteristics of TCGA CRC samples. The expression level of SLC2A1 in CRC was certified by cell experiments and immunohistochemical staining analysis. The Genome Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Gene Set Enrichment Analysis (GSEA) analyses of SLC2A1 relative genes were completed by bioinformatics analysis. The correlation between SLC2A1 expression level and CRC immune infiltration cell was analyzed by Tumor IMmune Estimation Resource (TIMER), Gene Expression Profiling Interactive Analysis (GEPIA), and TCGA database. The correlation between SLC2A1 expression level and ferroptosis and m6A modification of CRC was analyzed by utilizing TCGA and GEO cohort. Finally, the possible competing endogenous RNA (ceRNA) networks involved in SLC2A1 in CRC are predicted and constructed through various databases.Results: SLC2A1 is highly expressed not only in CRC but also in many other tumors. ROC curve indicated that SLC2A1 had high predictive accuracy for the outcomes of tumor. The SLC2A1 expression in CRC was closely correlated with tumor stage and progression free interval (PFI). GO, KEGG, and GSEA analysis indicated that SLC2A1 relative genes were involved in multiple biological functions. The analysis of TIMER, GEPIA, and TCGA database indicated that the SLC2A1 mRNA expression was mainly positively associated with neutrophils. By the analysis of the TCGA and GEO cohort, we identified that the expression of SLC2A1 is closely associated to an m6A modification relative gene Insulin Like Growth Factor 2 MRNA Binding Protein 3 (IGF2BP3) and a ferroptosis relative gene Glutathione Peroxidase 4 (GPX4).Conclusion: SLC2A1 can be used as a biomarker of CRC, which is associated to immune infiltration, m6A modification, ferroptosis, and ceRNA regulatory network of CRC.
Collapse
Affiliation(s)
- Xu-Sheng Liu
- Department of Nuclear Medicine and Institute of Anesthesiology and Pain, Taihe Hospital, Hubei University of Medicine, Shiyan, China
- *Correspondence: Xu-Sheng Liu, ; Zhi-Jun Pei,
| | - Jian-Wei Yang
- Department of Nuclear Medicine, Xiangyang Central Hospital, Affiliated Hospital of Hubei University of Arts and Science, Xiangyang, China
| | - Jing Zeng
- Department of Infection Control, Taihe Hospital, Hubei University of Medicine, Shiyan, China
| | | | - Yan Gao
- Department of Nuclear Medicine and Institute of Anesthesiology and Pain, Taihe Hospital, Hubei University of Medicine, Shiyan, China
| | - Xue-Yan Kui
- Department of Nuclear Medicine and Institute of Anesthesiology and Pain, Taihe Hospital, Hubei University of Medicine, Shiyan, China
| | - Xiao-Yu Liu
- Department of Nuclear Medicine and Institute of Anesthesiology and Pain, Taihe Hospital, Hubei University of Medicine, Shiyan, China
| | - Yu Zhang
- Department of Nuclear Medicine and Institute of Anesthesiology and Pain, Taihe Hospital, Hubei University of Medicine, Shiyan, China
| | - Yao-Hua Zhang
- Department of Nuclear Medicine and Institute of Anesthesiology and Pain, Taihe Hospital, Hubei University of Medicine, Shiyan, China
| | - Zhi-Jun Pei
- Department of Nuclear Medicine and Institute of Anesthesiology and Pain, Taihe Hospital, Hubei University of Medicine, Shiyan, China
- Hubei Clinical Research Center for Precise Diagnosis and Treatment of Liver Cancer, Taihe Hospital, Hubei University of Medicine, Shiyan, China
- *Correspondence: Xu-Sheng Liu, ; Zhi-Jun Pei,
| |
Collapse
|
|
15
|
Morales-Martínez M, Vega MI. Roles and Regulation of BCL-xL in Hematological Malignancies. Int J Mol Sci 2022; 23:2193. [PMID: 35216310 PMCID: PMC8876520 DOI: 10.3390/ijms23042193] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2022] [Revised: 02/10/2022] [Accepted: 02/11/2022] [Indexed: 12/20/2022] Open
Abstract
Members of the Bcl-2 family are proteins that play an essential role in the regulation of apoptosis, a crucial process in development and normal physiology in multicellular organisms. The essential mechanism of this family of proteins is given by the role of pro-survival proteins, which inhibit apoptosis by their direct binding with their counterpart, the effector proteins of apoptosis. This family of proteins was named after the typical member Bcl-2, which was named for its discovery and abnormal expression in B-cell lymphomas. Subsequently, the structure of one of its members BCL-xL was described, which allowed one to understand much of the molecular mechanism of this family. Due to its role of BCL-xL in the regulation of cell survival and proliferation, it has been of great interest in its study. Due to this, it is important to research its role regarding the development and progression of human malignancies, especially in hematologic malignancies. Due to its variation in expression in cancer, it has been suggested that BCL-xL can or cannot play a role in cancer depending on the cellular or tissue context. This review discusses recent advances in its transcriptional regulation of BCL-xL, as well as the advances regarding the activities of BCL-xL in hematological malignancies, its possible role as a biomarker, and its possible clinical relevance in these malignancies.
Collapse
Affiliation(s)
- Mario Morales-Martínez
- Molecular Signal Pathway in Cancer Laboratory, UIMEO, Oncology Hospital, Siglo XXI National Medical Center, IMSS, México City 06720, Mexico;
| | - Mario I. Vega
- Molecular Signal Pathway in Cancer Laboratory, UIMEO, Oncology Hospital, Siglo XXI National Medical Center, IMSS, México City 06720, Mexico;
- Department of Medicine, Hematology-Oncology Division, Greater Los Angeles VA Healthcare Center, UCLA Medical Center, Jonsson Comprehensive Cancer Center, Los Angeles, CA 90073, USA
| |
Collapse
|
|
16
|
Antonio-Andres G, Martinez-Ruiz GU, Morales-Martinez M, Jiménez-Hernandez E, Martinez-Torres E, Lopez-Perez TV, Estrada-Abreo LA, Patino-Lopez G, Juarez-Mendez S, Davila-Borja VM, Huerta-Yepez S. Transcriptional Regulation of Yin-Yang 1 Expression through the Hypoxia Inducible Factor-1 in Pediatric Acute Lymphoblastic Leukemia. Int J Mol Sci 2022; 23:ijms23031728. [PMID: 35163649 PMCID: PMC8835886 DOI: 10.3390/ijms23031728] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2021] [Revised: 01/09/2022] [Accepted: 01/11/2022] [Indexed: 12/04/2022] Open
Abstract
Yin-Yang transcription factor 1 (YY1) is involved in tumor progression, metastasis and has been shown to be elevated in different cancers, including leukemia. The regulatory mechanism underlying YY1 expression in leukemia is still not understood. Bioinformatics analysis reveal three Hypoxia-inducible factor 1-alpha (HIF-1α) putative binding sites in the YY1 promoter region. The regulation of YY1 by HIF-1α in leukemia was analyzed. Mutation of the putative YY1 binding sites in a reporter system containing the HIF-1α promoter region and CHIP analysis confirmed that these sites are important for YY1 regulation. Leukemia cell lines showed that both proteins HIF-1α and YY1 are co-expressed under hypoxia. In addition, the expression of mRNA of YY1 was increased after 3 h of hypoxia conditions and affect several target genes expression. In contrast, chemical inhibition of HIF-1α induces downregulation of YY1 and sensitizes cells to chemotherapeutic drugs. The clinical implications of HIF-1α in the regulation of YY1 were investigated by evaluation of expression of HIF-1α and YY1 in 108 peripheral blood samples and by RT-PCR in 46 bone marrow samples of patients with pediatric acute lymphoblastic leukemia (ALL). We found that the expression of HIF-1α positively correlates with YY1 expression in those patients. This is consistent with bioinformatic analyses of several databases. Our findings demonstrate for the first time that YY1 can be transcriptionally regulated by HIF-1α, and a correlation between HIF-1α expression and YY1 was found in ALL clinical samples. Hence, HIF-1α and YY1 may be possible therapeutic target and/or biomarkers of ALL.
Collapse
Affiliation(s)
- Gabriela Antonio-Andres
- Unidad de Investigación en Enfermedades Oncológicas, Hospital Infantil de México, Federico Gómez, Mexico City 06720, Mexico; (G.A.-A.); (M.M.-M.); (E.M.-T.); (T.V.L.-P.)
| | - Gustavo U. Martinez-Ruiz
- División de Investigación, Facultad de Medicina, Universidad Nacional Autónoma de México, Mexico City 04510, Mexico;
| | - Mario Morales-Martinez
- Unidad de Investigación en Enfermedades Oncológicas, Hospital Infantil de México, Federico Gómez, Mexico City 06720, Mexico; (G.A.-A.); (M.M.-M.); (E.M.-T.); (T.V.L.-P.)
| | - Elva Jiménez-Hernandez
- Servicio de Hemato-Oncología, Hospital Infantil de Moctezuma, Mexico City 15530, Mexico;
| | - Estefany Martinez-Torres
- Unidad de Investigación en Enfermedades Oncológicas, Hospital Infantil de México, Federico Gómez, Mexico City 06720, Mexico; (G.A.-A.); (M.M.-M.); (E.M.-T.); (T.V.L.-P.)
| | - Tania V. Lopez-Perez
- Unidad de Investigación en Enfermedades Oncológicas, Hospital Infantil de México, Federico Gómez, Mexico City 06720, Mexico; (G.A.-A.); (M.M.-M.); (E.M.-T.); (T.V.L.-P.)
- Consejo Nacional de Ciencia y Tecnología (CONACYT), Mexico City 03940, Mexico
| | - Laura A. Estrada-Abreo
- Laboratorio de Investigación en Inmunología y Proteómica, Hospital Infantil de México, Federico Gómez, Mexico City 06720, Mexico; (L.A.E.-A.); (G.P.-L.)
| | - Genaro Patino-Lopez
- Laboratorio de Investigación en Inmunología y Proteómica, Hospital Infantil de México, Federico Gómez, Mexico City 06720, Mexico; (L.A.E.-A.); (G.P.-L.)
| | - Sergio Juarez-Mendez
- Laboratorio de Oncología Experimental, Instituto Nacional de Pediatría, S.S.A., Mexico City 04530, Mexico; (S.J.-M.); (V.M.D.-B.)
| | - Víctor M. Davila-Borja
- Laboratorio de Oncología Experimental, Instituto Nacional de Pediatría, S.S.A., Mexico City 04530, Mexico; (S.J.-M.); (V.M.D.-B.)
| | - Sara Huerta-Yepez
- Unidad de Investigación en Enfermedades Oncológicas, Hospital Infantil de México, Federico Gómez, Mexico City 06720, Mexico; (G.A.-A.); (M.M.-M.); (E.M.-T.); (T.V.L.-P.)
- Correspondence: ; Tel.: +52-55-52289917 (ext. 4401); Fax: +52-55-44349663
| |
Collapse
|
|
17
|
Artificial Intelligence in Blood Transcriptomics. Artif Intell Med 2022. [DOI: 10.1007/978-3-030-64573-1_262] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
|
|
18
|
Tonc E, Takeuchi Y, Chou C, Xia Y, Holmgren M, Fujii C, Raju S, Chang GS, Iwamoto M, Egawa T. Unexpected suppression of tumorigenesis by c-MYC via TFAP4-dependent restriction of stemness in B lymphocytes. Blood 2021; 138:2526-2538. [PMID: 34283887 PMCID: PMC8678995 DOI: 10.1182/blood.2021011711] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2021] [Accepted: 07/10/2021] [Indexed: 11/20/2022] Open
Abstract
The proliferative burst of B lymphocytes is essential for antigen receptor repertoire diversification during the development and selective expansion of antigen-specific clones during immune responses. High proliferative activity inevitably promotes oncogenesis, the risk of which is further elevated in B lymphocytes by endogenous gene rearrangement and somatic mutations. However, B-cell-derived cancers are rare, perhaps owing to putative intrinsic tumor-suppressive mechanisms. We show that c-MYC facilitates B-cell proliferation as a protumorigenic driver and unexpectedly coengages counteracting tumor suppression through its downstream factor TFAP4. TFAP4 is mutated in human lymphoid malignancies, particularly in >10% of Burkitt lymphomas, and reduced TFAP4 expression was associated with poor survival of patients with MYC-high B-cell acute lymphoblastic leukemia. In mice, insufficient TFAP4 expression accelerated c-MYC-driven transformation of B cells. Mechanistically, c-MYC suppresses the stemness of developing B cells by inducing TFAP4 and restricting self-renewal of proliferating B cells. Thus, the pursuant transcription factor cascade functions as a tumor suppressor module that safeguards against the transformation of developing B cells.
Collapse
MESH Headings
- Animals
- B-Lymphocytes/metabolism
- B-Lymphocytes/pathology
- Carcinogenesis/genetics
- Carcinogenesis/pathology
- Cell Transformation, Neoplastic/genetics
- Cell Transformation, Neoplastic/pathology
- DNA-Binding Proteins/genetics
- Gene Expression Regulation, Neoplastic
- Genes, Tumor Suppressor
- Humans
- Leukemia, Lymphoid/genetics
- Leukemia, Lymphoid/pathology
- Lymphoma, B-Cell/genetics
- Lymphoma, B-Cell/pathology
- Mice, Inbred C57BL
- Mutation
- Proto-Oncogene Proteins c-myc/genetics
- Transcription Factors/genetics
- Tumor Cells, Cultured
- Mice
Collapse
Affiliation(s)
- Elena Tonc
- Department of Pathology and Immunology and
| | | | - Chun Chou
- Department of Pathology and Immunology and
| | - Yu Xia
- Department of Pathology and Immunology and
| | | | | | | | - Gue Su Chang
- McDonnell Genome Institute, Washington University School of Medicine, St Louis, MO; and
| | - Masahiro Iwamoto
- Department of Orthopaedics, University of Maryland, Baltimore, MD
| | | |
Collapse
|
|
19
|
Hong Y, Zhang L, Tian X, Xiang X, Yu Y, Zeng Z, Cao Y, Chen S, Sun A. Identification of immune subtypes of Ph-neg B-ALL with ferroptosis related genes and the potential implementation of Sorafenib. BMC Cancer 2021; 21:1331. [PMID: 34906116 PMCID: PMC8670244 DOI: 10.1186/s12885-021-09076-w] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2021] [Accepted: 11/30/2021] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND The clinical outcome of Philadelphia chromosome-negative B cell acute lymphoblastic leukemia (Ph-neg B-ALL) varies considerably from one person to another after clinical treatment due to lack of targeted therapies and leukemia's heterogeneity. Ferroptosis is a recently discovered programmed cell death strongly correlated with cancers. Nevertheless, few related studies have reported its significance in acute lymphoblastic leukemia. METHODS Herein, we collected clinical data of 80 Ph-neg B-ALL patients diagnosed in our center and performed RNA-seq with their initial bone marrow fluid samples. Throughout unsupervised machine learning K-means clustering with 24 ferroptosis related genes (FRGs), the clustered patients were parted into three variant risk groups and were performed with bioinformatics analysis. RESULTS As a result, we discovered significant heterogeneity of both immune microenvironment and genomic variance. Furthermore, the immune check point inhibitors response and potential implementation of Sorafenib in Ph-neg B-ALL was also analyzed in our cohort. Lastly, one prognostic model based on 8 FRGs was developed to evaluate the risk of Ph-neg B-ALL patients. CONCLUSION Jointly, our study proved the crucial role of ferroptosis in Ph-neg B-ALL and Sorafenib is likely to improve the survival of high-risk Ph-neg B-ALL patients.
Collapse
Affiliation(s)
- Yang Hong
- Department of Hematology, The First Affiliated Hospital of Soochow University, Jiangsu Institute of Hematology, National Clinical Research Center for Hematologic Diseases, Suzhou, China.,Institute of Blood and Marrow Transplantation, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China
| | - Ling Zhang
- Department of Hematology, The First Affiliated Hospital of Soochow University, Jiangsu Institute of Hematology, National Clinical Research Center for Hematologic Diseases, Suzhou, China.,Institute of Blood and Marrow Transplantation, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China
| | - Xiaopeng Tian
- Department of Hematology, The First Affiliated Hospital of Soochow University, Jiangsu Institute of Hematology, National Clinical Research Center for Hematologic Diseases, Suzhou, China.,Institute of Blood and Marrow Transplantation, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China
| | - Xin Xiang
- Department of Hematology, The First Affiliated Hospital of Soochow University, Jiangsu Institute of Hematology, National Clinical Research Center for Hematologic Diseases, Suzhou, China.,Institute of Blood and Marrow Transplantation, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China
| | - Yan Yu
- Department of Hematology, The First Affiliated Hospital of Soochow University, Jiangsu Institute of Hematology, National Clinical Research Center for Hematologic Diseases, Suzhou, China.,Institute of Blood and Marrow Transplantation, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China
| | - Zhao Zeng
- Department of Hematology, The First Affiliated Hospital of Soochow University, Jiangsu Institute of Hematology, National Clinical Research Center for Hematologic Diseases, Suzhou, China.,Institute of Blood and Marrow Transplantation, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China
| | - Yaqing Cao
- Department of Hematology, The First Affiliated Hospital of Soochow University, Jiangsu Institute of Hematology, National Clinical Research Center for Hematologic Diseases, Suzhou, China.,Institute of Blood and Marrow Transplantation, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China
| | - Suning Chen
- Department of Hematology, The First Affiliated Hospital of Soochow University, Jiangsu Institute of Hematology, National Clinical Research Center for Hematologic Diseases, Suzhou, China.,Institute of Blood and Marrow Transplantation, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China
| | - Aining Sun
- Department of Hematology, The First Affiliated Hospital of Soochow University, Jiangsu Institute of Hematology, National Clinical Research Center for Hematologic Diseases, Suzhou, China. .,Institute of Blood and Marrow Transplantation, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China.
| |
Collapse
|
|
20
|
Identification of an Immune-Related Biomarker Model Based on the CircRNA-Associated Regulatory Network for Esophageal Carcinoma. JOURNAL OF ONCOLOGY 2021; 2021:1334571. [PMID: 34840568 PMCID: PMC8612787 DOI: 10.1155/2021/1334571] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/27/2021] [Accepted: 11/03/2021] [Indexed: 12/14/2022]
Abstract
Esophageal carcinoma (ESCA) is one of the most frequent types of malignant tumor that has a dismal prognosis. This research applied datasets aimed from the GEO and TCGA to create a prognostic signature for forecasting the clinical outcome of ESCA patients on the basis of a circRNA-associated regulatory network. Methods. A regulatory network associated with ESCA was established based on transcriptome data of circRNAs, miRNAs, and mRNAs. Functional annotations were implemented to further explore the mechanism of ESCA. Cox relative regression method was applied to create a risk signature. Besides, the immune microenvironment of the signature was investigated by utilizing the CIBERSORT algorithm. Results. Based on 27 DEcircRNAs, 65 DEmiRNAs, and 780 DEmRNAs, the circRNA-miRNA-mRNA network was finally set up. Functional enrichment unearthed that the regulatory network might participate in phosphorylation negative regulation, MAPK pathway, and PI3K/AKT pathway. This study established a risk scoring signature based on the seven immune-related genes (IRGs) (MARP14, RASGR1, PTK2, HMGB1, DKK1, RARB, and IGF1R), which was validated for its reliability. A stable and accurate nomogram combining immune-related risk scores with clinical features was constructed. Furthermore, we observed that the risk model was also related to the immunocyte infiltration. Conclusion. Our study successfully created a circRNA-associated regulatory network and further developed an immune-related model to forecast the clinical outcome of ESCA patients as well as to assess their immune status.
Collapse
|
|
21
|
Zhang W, Zhang W, Gui L, Yan X, Zhou X, Ma Y, Yang Z, Fang Y, Zhang H, Shi J. Expression and prognosis of the B7 family in acute myeloid leukemia. ANNALS OF TRANSLATIONAL MEDICINE 2021; 9:1530. [PMID: 34790736 PMCID: PMC8576715 DOI: 10.21037/atm-21-4255] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/03/2021] [Accepted: 09/09/2021] [Indexed: 12/21/2022]
Abstract
Background B7 family molecules affect both immune responses and cancer progression via immunological and non-immunological pathways. However, the specific expression and prognostic value of B7 members in acute myeloid leukemia (AML) remains unclear; hence, an investigation using online bioinformatics databases is required. Methods In this study, we explored the expression of B7 molecules using the ONCOMINE, Gene Expression Profiling Interactive Analysis 2 (GEPIA2), and UALCAN databases, while the prognostic value of B7 molecules in AML was analyzed using the LinkedOmics, GEPIA2, UALCAN, and TCGAportal databases. Additionally, genetic alteration and gene co-expression analysis of the B7 family was performed via the cBioPortal and LinkedOmics databases, while functional and pathway enrichment analyses were conducted using the Metascape databases for Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses. Results The message RNA (mRNA) levels of B7 family members varied in AML patients, and aberrant highly expressed B7 members were correlated with poor prognosis in AML, including B7.1, B7-DC, B7-H3, B7-H5, and B7-H7. B7-H6 acted as a protective molecule for overall survival (OS), while B7-H1 overexpression was inclined to predict poor prognosis. B7 family gene alteration occurred frequently in AML, and the altered B7 group seemed to exhibit a trend towards worse OS. The co-expression genes and relative signaling pathways of the B7 family might be involved in oncogenesis and be associated with prognosis in AML. Conclusions Our study showed that aberrantly expressed B7 family molecules affected the prognosis of AML patients, and thus, could be promising prognostic biomarkers and new therapeutic targets.
Collapse
Affiliation(s)
- Wei Zhang
- Department of Hematology, The Affiliated Jiangning Hospital with Nanjing Medical University, Nanjing, China
| | - Wenjing Zhang
- Department of Hematology, The Affiliated Jiangning Hospital with Nanjing Medical University, Nanjing, China
| | - Lin Gui
- Department of Hematology, The Affiliated Jiangning Hospital with Nanjing Medical University, Nanjing, China
| | - Xue Yan
- Department of Hematology, The Affiliated Jiangning Hospital with Nanjing Medical University, Nanjing, China
| | - Xuan Zhou
- Department of Hematology, The Affiliated Jiangning Hospital with Nanjing Medical University, Nanjing, China
| | - Yongchao Ma
- Department of Hematology, The Affiliated Jiangning Hospital with Nanjing Medical University, Nanjing, China
| | - Zhinan Yang
- Department of Hematology, The Affiliated Jiangning Hospital with Nanjing Medical University, Nanjing, China
| | - Yu Fang
- Department of Hematology, The Affiliated Jiangning Hospital with Nanjing Medical University, Nanjing, China
| | - Hongmei Zhang
- Department of Blood Transfusion, The Affiliated Jiangning Hospital with Nanjing Medical University, Nanjing, China
| | - Jinning Shi
- Department of Hematology, The Affiliated Jiangning Hospital with Nanjing Medical University, Nanjing, China
| |
Collapse
|
|
22
|
Cuesta-Mateos C, Terrón F, Herling M. CCR7 in Blood Cancers - Review of Its Pathophysiological Roles and the Potential as a Therapeutic Target. Front Oncol 2021; 11:736758. [PMID: 34778050 PMCID: PMC8589249 DOI: 10.3389/fonc.2021.736758] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2021] [Accepted: 10/12/2021] [Indexed: 11/23/2022] Open
Abstract
According to the classical paradigm, CCR7 is a homing chemokine receptor that grants normal lymphocytes access to secondary lymphoid tissues such as lymph nodes or spleen. As such, in most lymphoproliferative disorders, CCR7 expression correlates with nodal or spleen involvement. Nonetheless, recent evidence suggests that CCR7 is more than a facilitator of lymphatic spread of tumor cells. Here, we review published data to catalogue CCR7 expression across blood cancers and appraise which classical and novel roles are attributed to this receptor in the pathogenesis of specific hematologic neoplasms. We outline why novel therapeutic strategies targeting CCR7 might provide clinical benefits to patients with CCR7-positive hematopoietic tumors.
Collapse
Affiliation(s)
- Carlos Cuesta-Mateos
- Immunology Department, Hospital Universitario de La Princesa, Instituto de Investigación Sanitaria- Instituto la Princesa (IIS-IP), Madrid, Spain.,Immunological and Medicinal Products (IMMED S.L.), Madrid, Spain.,Catapult Therapeutics BV, Lelystad, Netherlands
| | - Fernando Terrón
- Immunological and Medicinal Products (IMMED S.L.), Madrid, Spain.,Catapult Therapeutics BV, Lelystad, Netherlands
| | - Marco Herling
- Clinic of Hematology and Cellular Therapy, University of Leipzig, Leipzig, Germany
| |
Collapse
|
|
23
|
Liu XS, Liu JM, Chen YJ, Li FY, Wu RM, Tan F, Zeng DB, Li W, Zhou H, Gao Y, Pei ZJ. Comprehensive Analysis of Hexokinase 2 Immune Infiltrates and m6A Related Genes in Human Esophageal Carcinoma. Front Cell Dev Biol 2021; 9:715883. [PMID: 34708035 PMCID: PMC8544599 DOI: 10.3389/fcell.2021.715883] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2021] [Accepted: 09/17/2021] [Indexed: 12/16/2022] Open
Abstract
Background: Hexokinase 2 not only plays a role in physiological function of human normal tissues and organs, but also plays a vital role in the process of glycolysis of tumor cells. However, there are few comprehensive studies on HK2 in esophageal carcinoma (ESCA) needs further study. Methods: Oncomine, Tumor Immune Estimation Resource (TIMER), The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) database were used to analyze the expression differences of HK2 in Pan-cancer and ESCA cohort, and to analyze the correlation between HK2 expression level and clinicopathological features of TCGA ESCA samples. GO/KEGG, GGI, and PPI analysis of HK2 was performed using R software, LinkedOmics, GeneMANIA and STRING online tools. The correlation between HK2 and ESCA immune infiltration was analyzed TIMER and TCGA ESCA cohort. The correlation between HK2 expression level and m6A modification of ESCA was analyzed by utilizing TCGA ESCA cohort. Results: HK2 is highly expressed in a variety of tumors, and its high expression level in ESCA is closely related to the weight, cancer stages, tumor histology and tumor grade of ESCA. The analysis results of GO/KEGG showed that HK2 was closely related to cell adhesion molecule binding, cell-cell junction, ameboidal-type cell migration, insulin signaling pathway, hif-1 signaling pathway, and insulin resistance. GGI showed that HK2 associated genes were mainly involved in the glycolytic pathway. PPI showed that HK2 was closely related to HK1, GPI, and HK3, all of which played an important role in tumor proliferation. The analysis results of TIMER and TCGA ESCA cohort indicated that the HK2 expression level was related to the infiltration of various immune cells. TCGA ESCA cohort analyze indicated that the HK2 expression level was correlated with m6A modification genes. Conclusion: HK2 is associated with tumor immune infiltration and m6A modification of ESCA, and can be used as a potential biological target for diagnosis and therapy of ESCA.
Collapse
Affiliation(s)
- Xu-Sheng Liu
- Department of Nuclear Medicine and Institute of Anesthesiology and Pain, Taihe Hospital, Hubei University of Medicine, Shiyan, China.,Hubei Clinical Research Center for Precise Diagnosis and Treatment of Liver Cancer, Taihe Hospital, Hubei University of Medicine, Shiyan, China
| | - Jia-Min Liu
- Shiyan Emergency Medical Center, Shiyan, China.,School of Public Health, Hubei University of Medicine, Shiyan, China
| | - Yi-Jia Chen
- Department of Nuclear Medicine and Institute of Anesthesiology and Pain, Taihe Hospital, Hubei University of Medicine, Shiyan, China
| | - Fu-Yan Li
- Department of Nuclear Medicine and Institute of Anesthesiology and Pain, Taihe Hospital, Hubei University of Medicine, Shiyan, China
| | - Rui-Min Wu
- Department of Nuclear Medicine and Institute of Anesthesiology and Pain, Taihe Hospital, Hubei University of Medicine, Shiyan, China
| | - Fan Tan
- Department of Nuclear Medicine and Institute of Anesthesiology and Pain, Taihe Hospital, Hubei University of Medicine, Shiyan, China
| | - Dao-Bing Zeng
- Department of Nuclear Medicine and Institute of Anesthesiology and Pain, Taihe Hospital, Hubei University of Medicine, Shiyan, China
| | - Wei Li
- Department of Nuclear Medicine and Institute of Anesthesiology and Pain, Taihe Hospital, Hubei University of Medicine, Shiyan, China
| | - Hong Zhou
- Department of Nuclear Medicine and Institute of Anesthesiology and Pain, Taihe Hospital, Hubei University of Medicine, Shiyan, China
| | - Yan Gao
- Department of Nuclear Medicine and Institute of Anesthesiology and Pain, Taihe Hospital, Hubei University of Medicine, Shiyan, China
| | - Zhi-Jun Pei
- Department of Nuclear Medicine and Institute of Anesthesiology and Pain, Taihe Hospital, Hubei University of Medicine, Shiyan, China.,Hubei Clinical Research Center for Precise Diagnosis and Treatment of Liver Cancer, Taihe Hospital, Hubei University of Medicine, Shiyan, China
| |
Collapse
|
|
24
|
Overview of Human HtrA Family Proteases and Their Distinctive Physiological Roles and Unique Involvement in Diseases, Especially Cancer and Pregnancy Complications. Int J Mol Sci 2021; 22:ijms221910756. [PMID: 34639128 PMCID: PMC8509474 DOI: 10.3390/ijms221910756] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2021] [Revised: 09/27/2021] [Accepted: 10/02/2021] [Indexed: 12/25/2022] Open
Abstract
The mammalian high temperature requirement A (HtrA) proteins are a family of evolutionarily conserved serine proteases, consisting of four homologs (HtrA1-4) that are involved in many cellular processes such as growth, unfolded protein stress response and programmed cell death. In humans, while HtrA1, 2 and 3 are widely expressed in multiple tissues with variable levels, HtrA4 expression is largely restricted to the placenta with the protein released into maternal circulation during pregnancy. This limited expression sets HtrA4 apart from the rest of the family. All four HtrAs are active proteases, and their specific cellular and physiological roles depend on tissue type. The dysregulation of HtrAs has been implicated in many human diseases such as cancer, arthritis, neurogenerative ailments and reproductive disorders. This review first discusses HtrAs broadly and then focuses on the current knowledge of key molecular characteristics of individual human HtrAs, their similarities and differences and their reported physiological functions. HtrAs in other species are also briefly mentioned in the context of understanding the human HtrAs. It then reviews the distinctive involvement of each HtrA in various human diseases, especially cancer and pregnancy complications. It is noteworthy that HtrA4 expression has not yet been reported in any primary tumour samples, suggesting an unlikely involvement of this HtrA in cancer. Collectively, we accentuate that a better understanding of tissue-specific regulation and distinctive physiological and pathological roles of each HtrA will improve our knowledge of many processes that are critical for human health.
Collapse
|
|
25
|
SCAMP2/5 as diagnostic and prognostic markers for acute myeloid leukemia. Sci Rep 2021; 11:17012. [PMID: 34426610 PMCID: PMC8382833 DOI: 10.1038/s41598-021-96440-2] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2021] [Accepted: 08/09/2021] [Indexed: 01/04/2023] Open
Abstract
The secretory carrier-associated membrane proteins (SCAMPs) are associated with the development of multiple human cancers. The role of SCAMPs in acute myeloid leukemia (AML), however, remains to be identified. In the present study, we explored expression patterns and prognostic value of SCAMPs and network analysis of SCAMPs-related signaling pathways in AML using Oncomine, GEPIA, cBioPortal, LinkedOmics, DAVID and Metascape databases. Genetic alteration analysis revealed that the mutation rate of SCAMP genes was below 1% (9/1272) in AML, and there was no significant correlation between SCAMPs gene mutation and AML prognosis. However, the SCAMP2/5 mRNA levels were significantly higher in AML patients than in healthy controls. Moreover, high mRNA expressions of SCAMP2/4/5 were associated with poor overall survival, which might be due to that SCAMP2/4/5 and their co-expressed genes were associated with multiple pathways related to tumorigenesis and progression, including human T-cell leukemia virus 1 infection, acute myeloid leukemia, mTOR and NF-kappa B signaling pathways. These results suggest that SCAMP2/4/5 are potential prognostic markers for AML, and that SCAMP2 and SCAMP5 individually or in combination may be used as diagnostic markers for AML.
Collapse
|
|
26
|
López-Ozuna VM, Kogan L, Hachim MY, Matanes E, Hachim IY, Mitric C, Kiow LLC, Lau S, Salvador S, Yasmeen A, Gotlieb WH. Identification of Predictive Biomarkers for Lymph Node Involvement in Obese Women With Endometrial Cancer. Front Oncol 2021; 11:695404. [PMID: 34307159 PMCID: PMC8292832 DOI: 10.3389/fonc.2021.695404] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2021] [Accepted: 06/23/2021] [Indexed: 11/13/2022] Open
Abstract
Obesity, an established risk factor for endometrial cancer (EC), is also associated to increased risks of intraoperative and postoperative complications. A reliable tool to identify patients at low risk for lymph node (LN) metastasis may allow minimizing the surgical staging and omit lymphadenectomy in obese patients. To identify molecular biomarkers that could predict LN involvement in obese patients with EC we performed gene expression analysis in 549 EC patients using publicly available transcriptomic datasets. Patients were filtrated according to cancer subtype, weight (>30 kg/m2) and LN status. While in the LN+ group, NEB, ANK1, AMIGO2, LZTS1, FKBP5, CHGA, USP32P1, CLIC6, CEMIP, HMCN1 and TNFRSF10C genes were highly expressed; in the LN- group CXCL14, FCN1, EPHX3, DDX11L2, TMEM254, RNF207, LTK, RPL36A, HGAL, B4GALNT4, KLRG1 genes were up-regulated. As a second step, we investigated these genes in our patient cohort of 35 patients (15 LN+ and 20 LN-) and found the same correlation with the in-silico analysis. In addition, immunohistochemical expression was confirmed in the tumor tissue. Altogether, our findings propose a novel panel of genes able to predict LN involvement in obese patients with endometrial cancer.
Collapse
Affiliation(s)
- Vanessa M López-Ozuna
- Division of Gynecologic Oncology, Jewish General Hospital, McGill University, Montreal, QC, Canada.,Segal Cancer Center, Lady Davis Institute of Medical Research, McGill University, Montreal, QC, Canada
| | - Liron Kogan
- Division of Gynecologic Oncology, Jewish General Hospital, McGill University, Montreal, QC, Canada.,Department of Gynecologic Oncology, Hadassah Medical Center, affiliated with Hebrew University Hadassah Medical School, Jerusalem, Israel
| | - Mahmood Y Hachim
- College of Medicine, Mohammed Bin Rashid University of Medicine and Health Sciences, Dubai, United Arab Emirates
| | - Emad Matanes
- Division of Gynecologic Oncology, Jewish General Hospital, McGill University, Montreal, QC, Canada.,Segal Cancer Center, Lady Davis Institute of Medical Research, McGill University, Montreal, QC, Canada
| | - Ibrahim Y Hachim
- College of Medicine, Sharjah Institute for Medical Research, University of Sharjah, Sharjah, United Arab Emirates
| | - Cristina Mitric
- Division of Gynecologic Oncology, Jewish General Hospital, McGill University, Montreal, QC, Canada.,Segal Cancer Center, Lady Davis Institute of Medical Research, McGill University, Montreal, QC, Canada
| | - Lauren Liu Chen Kiow
- Division of Gynecologic Oncology, Jewish General Hospital, McGill University, Montreal, QC, Canada.,Segal Cancer Center, Lady Davis Institute of Medical Research, McGill University, Montreal, QC, Canada
| | - Susie Lau
- Division of Gynecologic Oncology, Jewish General Hospital, McGill University, Montreal, QC, Canada.,Segal Cancer Center, Lady Davis Institute of Medical Research, McGill University, Montreal, QC, Canada
| | - Shannon Salvador
- Division of Gynecologic Oncology, Jewish General Hospital, McGill University, Montreal, QC, Canada.,Segal Cancer Center, Lady Davis Institute of Medical Research, McGill University, Montreal, QC, Canada
| | - Amber Yasmeen
- Division of Gynecologic Oncology, Jewish General Hospital, McGill University, Montreal, QC, Canada.,Segal Cancer Center, Lady Davis Institute of Medical Research, McGill University, Montreal, QC, Canada
| | - Walter H Gotlieb
- Division of Gynecologic Oncology, Jewish General Hospital, McGill University, Montreal, QC, Canada.,Segal Cancer Center, Lady Davis Institute of Medical Research, McGill University, Montreal, QC, Canada
| |
Collapse
|
|
27
|
Hu J, Wang T, Xu J, Wu S, Wang L, Su H, Jiang J, Yue M, Wang J, Wang D, Li P, Zhou F, Liu Y, Qing G, Liu H. WEE1 inhibition induces glutamine addiction in T-cell acute lymphoblastic leukemia. Haematologica 2021; 106:1816-1827. [PMID: 31919076 PMCID: PMC8252940 DOI: 10.3324/haematol.2019.231126] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2019] [Indexed: 12/13/2022] Open
Abstract
Tcell acute lymphoblastic leukemias (T-ALL) are aggressive and heterogeneous hematologic tumors resulting from the malignant transformation of T-cell progenitors. The major challenges in the treatment of T-ALL are dose-limiting toxicities of chemotherapeutics and drug resistance. Despite important progress in deciphering the genomic landscape of T-ALL, translation of these findings into effective targeted therapies remains largely unsuccessful. New targeted agents with significant antileukemic efficacy and less toxicity are urgently needed. Here we report that the expression of WEE1, a nuclear tyrosine kinase involved in cell cycle G2-M checkpoint signaling, is significantly elevated in T-ALL. Mechanistically, oncogenic MYC directly binds to the WEE1 promoter and activates its transcription. T-ALL cells particularly rely on the elevated WEE1 for cell viability. Pharmacological inhibition of WEE1 elicits global metabolic reprogramming which results in a marked suppression of aerobic glycolysis in T-ALL cells, leading to an increased dependency on glutaminolysis for cell survival. As such, dual targeting of WEE1 and glutaminase (GLS1) induces synergistic lethality in multiple TALL cell lines and shows great efficacy in T-ALL patient-derived xenografts. These findings provide mechanistic insights into the regulation of WEE1 kinase in T-ALL and suggest an additional vulnerability during WEE1 inhibitor treatments. We also highlight a promising combination strategy of dual inhibition of cell cycle kinase and metabolic enzymes for T-ALL therapeutics.
Collapse
Affiliation(s)
- Juncheng Hu
- Zhongnan Hospital, Wuhan University, Wuhan, China
| | - Tianci Wang
- Zhongnan Hospital, Wuhan University, Wuhan, China
| | - Jin Xu
- Medical Research Institute, Wuhan University, Wuhan, China
| | - Sanyun Wu
- Department of Hematology, Zhongnan Hospital, Wuhan University, Wuhan, China
| | - Liyuan Wang
- Medical Research Institute, Wuhan University, Wuhan, China
| | - Hexiu Su
- Medical Research Institute, Wuhan University, Wuhan, China
| | - Jue Jiang
- Medical Research Institute, Wuhan University, Wuhan, China
| | - Ming Yue
- Department of Pharmacy, The Central Hospital of Wuhan, Wuhan, China
| | - Jingchao Wang
- Medical Research Institute, Wuhan University, Wuhan, China
| | - Donghai Wang
- Medical Research Institute, Wuhan University, Wuhan, China
| | - Peng Li
- Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China
| | - Fuling Zhou
- Department of Hematology, Zhongnan Hospital, Wuhan University, Wuhan, China
| | - Yu Liu
- Shanghai Children Medical Center, Shanghai Jiao Tong University School of Medicine, China
| | - Guoliang Qing
- Medical Research Institute, Wuhan University, Wuhan, China
| | - Hudan Liu
- Zhongnan Hospital, Wuhan University, Wuhan, China
| |
Collapse
|
|
28
|
Song X, Wang L, Wang T, Hu J, Wang J, Tu R, Su H, Jiang J, Qing G, Liu H. Synergistic targeting of CHK1 and mTOR in MYC-driven tumors. Carcinogenesis 2021; 42:448-460. [PMID: 33206174 DOI: 10.1093/carcin/bgaa119] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2020] [Revised: 10/22/2020] [Accepted: 11/12/2020] [Indexed: 12/22/2022] Open
Abstract
Deregulation of v-myc avian myelocytomatosis viral oncogene homolog (MYC) occurs in a broad range of human cancers and often predicts poor prognosis and resistance to therapy. However, directly targeting oncogenic MYC remains unsuccessful, and indirectly inhibiting MYC emerges as a promising approach. Checkpoint kinase 1 (CHK1) is a protein kinase that coordinates the G2/M cell cycle checkpoint and protects cancer cells from excessive replicative stress. Using c-MYC-mediated T-cell acute lymphoblastic leukemia (T-acute lymphoblastic leukemia) and N-MYC-driven neuroblastoma as model systems, we reveal that both c-MYC and N-MYC directly bind to the CHK1 locus and activate its transcription. CHIR-124, a selective CHK1 inhibitor, impairs cell viability and induces remarkable synergistic lethality with mTOR inhibitor rapamycin in MYC-overexpressing cells. Mechanistically, rapamycin inactivates carbamoyl-phosphate synthetase 2, aspartate transcarbamoylase, and dihydroorotase (CAD), the essential enzyme for the first three steps of de novo pyrimidine synthesis, and deteriorates CHIR-124-induced replicative stress. We further demonstrate that dual treatments impede T-acute lymphoblastic leukemia and neuroblastoma progression in vivo. These results suggest simultaneous targeting of CHK1 and mTOR as a novel and powerful co-treatment modality for MYC-mediated tumors.
Collapse
Affiliation(s)
- Xiaoxue Song
- Department of Hematology, Zhongnan Hospital of Wuhan University, Wuhan, P. R. China.,Frontier Science Center for Immunology and Metabolism, Medical Research Institute, Wuhan University, Wuhan, P. R. China
| | - Liyuan Wang
- Department of Hematology, Zhongnan Hospital of Wuhan University, Wuhan, P. R. China.,Frontier Science Center for Immunology and Metabolism, Medical Research Institute, Wuhan University, Wuhan, P. R. China
| | - Tianci Wang
- Frontier Science Center for Immunology and Metabolism, Medical Research Institute, Wuhan University, Wuhan, P. R. China
| | - Juncheng Hu
- Frontier Science Center for Immunology and Metabolism, Medical Research Institute, Wuhan University, Wuhan, P. R. China
| | - Jingchao Wang
- Frontier Science Center for Immunology and Metabolism, Medical Research Institute, Wuhan University, Wuhan, P. R. China
| | - Rongfu Tu
- Frontier Science Center for Immunology and Metabolism, Medical Research Institute, Wuhan University, Wuhan, P. R. China
| | - Hexiu Su
- Frontier Science Center for Immunology and Metabolism, Medical Research Institute, Wuhan University, Wuhan, P. R. China
| | - Jue Jiang
- Frontier Science Center for Immunology and Metabolism, Medical Research Institute, Wuhan University, Wuhan, P. R. China
| | - Guoliang Qing
- Frontier Science Center for Immunology and Metabolism, Medical Research Institute, Wuhan University, Wuhan, P. R. China
| | - Hudan Liu
- Department of Hematology, Zhongnan Hospital of Wuhan University, Wuhan, P. R. China.,Frontier Science Center for Immunology and Metabolism, Medical Research Institute, Wuhan University, Wuhan, P. R. China
| |
Collapse
|
|
29
|
Liu XS, Gao Y, Wu LB, Wan HB, Yan P, Jin Y, Guo SB, Wang YL, Chen XQ, Zhou LM, Yang JW, Kui XY, Liu XY, Pei ZJ. Comprehensive Analysis of GLUT1 Immune Infiltrates and ceRNA Network in Human Esophageal Carcinoma. Front Oncol 2021; 11:665388. [PMID: 34123828 PMCID: PMC8195627 DOI: 10.3389/fonc.2021.665388] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2021] [Accepted: 05/05/2021] [Indexed: 12/11/2022] Open
Abstract
Background Glucose transporter 1 (GLUT1) is encoded by the solute carrier family 2A1 (SLC2A1) gene and is one of the glucose transporters with the greatest affinity for glucose. Abnormal expression of GLUT1 is associated with a variety of cancers. However, the biological role of GLUT1 in esophageal carcinoma (ESCA) remains to be determined. Methods We analyzed the expression of GLUT1 in pan-cancer and ESCA as well as clinicopathological analysis through multiple databases. Use R and STRING to perform GO/KEGG function enrichment and PPI analysis for GLUT1 co-expression. TIMER and CIBERSORT were used to analyze the relationship between GLUT1 expression and immune infiltration in ESCA. The TCGA ESCA cohort was used to analyze the relationship between GLUT1 expression and m6A modification in ESCA, and to construct a regulatory network in line with the ceRNA hypothesis. Results GLUT1 is highly expressed in a variety of tumors including ESCA, and is closely related to histological types and histological grade. GO/KEGG functional enrichment analysis revealed that GLUT1 is closely related to structural constituent of cytoskeleton, intermediate filament binding, cell-cell adheres junction, epidermis development, and P53 signaling pathway. PPI shows that GLUT1 is closely related to TP53, GIPC1 and INS, and these three proteins all play an important role in tumor proliferation. CIBERSORT analysis showed that GLUT1 expression is related to the infiltration of multiple immune cells. When GLUT1 is highly expressed, the number of memory B cells decreases. ESCA cohort analysis found that GLUT1 expression was related to 7 m6A modifier genes. Six possible crRNA networks in ESCA were constructed by correlation analysis, and all these ceRNA networks contained GLUT1. Conclusion GLUT1 can be used as a biomarker for the diagnosis and treatment of ESCA, and is related to tumor immune infiltration, m6A modification and ceRNA network.
Collapse
Affiliation(s)
- Xu-Sheng Liu
- Department of Nuclear Medicine and Institute of Anesthesiology and Pain, Taihe Hospital, Hubei University of Medicine, Shiyan, China
| | - Yan Gao
- Department of Nuclear Medicine and Institute of Anesthesiology and Pain, Taihe Hospital, Hubei University of Medicine, Shiyan, China
| | - Li-Bing Wu
- Department of Nuclear Medicine and Institute of Anesthesiology and Pain, Taihe Hospital, Hubei University of Medicine, Shiyan, China
| | - Hua-Bing Wan
- Department of Nuclear Medicine and Institute of Anesthesiology and Pain, Taihe Hospital, Hubei University of Medicine, Shiyan, China
| | - Peng Yan
- Department of Nuclear Medicine and Institute of Anesthesiology and Pain, Taihe Hospital, Hubei University of Medicine, Shiyan, China
| | - Yang Jin
- Department of Nuclear Medicine and Institute of Anesthesiology and Pain, Taihe Hospital, Hubei University of Medicine, Shiyan, China
| | - Shi-Bo Guo
- Department of Nuclear Medicine and Institute of Anesthesiology and Pain, Taihe Hospital, Hubei University of Medicine, Shiyan, China
| | - Ya-Lan Wang
- Department of Nuclear Medicine and Institute of Anesthesiology and Pain, Taihe Hospital, Hubei University of Medicine, Shiyan, China
| | | | - Lu-Meng Zhou
- Department of Nuclear Medicine and Institute of Anesthesiology and Pain, Taihe Hospital, Hubei University of Medicine, Shiyan, China
| | - Jian-Wei Yang
- Department of Nuclear Medicine and Institute of Anesthesiology and Pain, Taihe Hospital, Hubei University of Medicine, Shiyan, China
| | - Xue-Yan Kui
- Department of Nuclear Medicine and Institute of Anesthesiology and Pain, Taihe Hospital, Hubei University of Medicine, Shiyan, China
| | - Xiao-Yu Liu
- Department of Nuclear Medicine and Institute of Anesthesiology and Pain, Taihe Hospital, Hubei University of Medicine, Shiyan, China
| | - Zhi-Jun Pei
- Department of Nuclear Medicine and Institute of Anesthesiology and Pain, Taihe Hospital, Hubei University of Medicine, Shiyan, China.,Hubei Key Laboratory of Embryonic Stem Cell Research, Shiyan, China
| |
Collapse
|
|
30
|
Depreter B, De Moerloose B, Vandepoele K, Uyttebroeck A, Van Damme A, Terras E, Denys B, Dedeken L, Dresse MF, Van der Werff Ten Bosch J, Hofmans M, Philippé J, Lammens T. Deciphering molecular heterogeneity in pediatric AML using a cancer vs. normal transcriptomic approach. Pediatr Res 2021; 89:1695-1705. [PMID: 33069162 DOI: 10.1038/s41390-020-01199-3] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/13/2020] [Revised: 07/30/2020] [Accepted: 09/25/2020] [Indexed: 11/10/2022]
Abstract
BACKGROUND Still 30-40% of pediatric acute myeloid leukemia (pedAML) patients relapse. Delineation of the transcriptomic profile of leukemic subpopulations could aid in a better understanding of molecular biology and provide novel biomarkers. METHODS Using microarray profiling and quantitative PCR validation, transcript expression was measured in leukemic stem cells (LSC, n = 24) and leukemic blasts (L-blast, n = 25) from pedAML patients in comparison to hematopoietic stem cells (HSCs, n = 19) and control myeloblasts (C-blast, n = 20) sorted from healthy subjects. Gene set enrichment analysis was performed to identify relevant gene set enrichment signatures, and functional protein associations were identified by STRING analysis. RESULTS Highly significantly overexpressed genes in LSC and L-blast were identified with a vast majority not studied in AML. CDKN1A, CFP, and CFD (LSC) and HOMER3, CTSA, and GADD45B (L-blast) represent potentially interesting biomarkers and therapeutic targets. Eleven LSC downregulated targets were identified that potentially qualify as tumor suppressor genes, with MYCT1, PBX1, and PTPRD of highest interest. Inflammatory and immune dysregulation appeared to be perturbed biological networks in LSC, whereas dysregulated metabolic profiles were observed in L-blast. CONCLUSION Our study illustrates the power of taking into account cell population heterogeneity and reveals novel targets eligible for functional evaluation and therapy in pedAML. IMPACT Novel transcriptional targets were discovered showing a significant differential expression in LSCs and blasts from pedAML patients compared to their normal counterparts from healthy controls. Deregulated pathways, including immune and metabolic dysregulation, were addressed for the first time in children, offering a deeper understanding of the molecular pathogenesis. These novel targets have the potential of acting as biomarkers for risk stratification, follow-up, and targeted therapy. Multiple LSC-downregulated targets endow tumor suppressor roles in other cancer entities, and further investigation whether hypomethylating therapy could result into LSC eradication in pedAML is warranted.
Collapse
Affiliation(s)
- Barbara Depreter
- Department of Internal Medicine and Pediatrics, Ghent University, Ghent, Belgium.
| | - Barbara De Moerloose
- Department of Internal Medicine and Pediatrics, Ghent University, Ghent, Belgium.,Cancer Research Institute Ghent, Ghent, Belgium.,Department of Pediatric Hematology-Oncology and Stem Cell Transplantation, Ghent University Hospital, Ghent, Belgium
| | - Karl Vandepoele
- Cancer Research Institute Ghent, Ghent, Belgium.,Department of Laboratory Medicine, Ghent University Hospital, Ghent, Belgium
| | - Anne Uyttebroeck
- Department of Pediatrics, University Hospital Gasthuisberg, Leuven, Belgium
| | - An Van Damme
- Department of Pediatric Hematology Oncology, University Hospital Saint-Luc, Brussels, Belgium
| | - Eva Terras
- Department of Pediatric Hematology-Oncology and Stem Cell Transplantation, Ghent University Hospital, Ghent, Belgium
| | - Barbara Denys
- Department of Laboratory Medicine, Ghent University Hospital, Ghent, Belgium
| | - Laurence Dedeken
- Department of Pediatric Hematology Oncology, Queen Fabiola Children's University Hospital, Brussels, Belgium
| | | | | | - Mattias Hofmans
- Department of Internal Medicine and Pediatrics, Ghent University, Ghent, Belgium.,Cancer Research Institute Ghent, Ghent, Belgium
| | - Jan Philippé
- Cancer Research Institute Ghent, Ghent, Belgium.,Department of Laboratory Medicine, Ghent University Hospital, Ghent, Belgium.,Department of Diagnostic Sciences, Ghent University, Ghent, Belgium
| | - Tim Lammens
- Department of Internal Medicine and Pediatrics, Ghent University, Ghent, Belgium.,Cancer Research Institute Ghent, Ghent, Belgium.,Department of Pediatric Hematology-Oncology and Stem Cell Transplantation, Ghent University Hospital, Ghent, Belgium
| |
Collapse
|
|
31
|
Morales-Martinez M, Lichtenstein A, Vega MI. Function of Deptor and its roles in hematological malignancies. Aging (Albany NY) 2021; 13:1528-1564. [PMID: 33412518 PMCID: PMC7834987 DOI: 10.18632/aging.202462] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2020] [Accepted: 12/10/2020] [Indexed: 12/12/2022]
Abstract
Deptor is a protein that interacts with mTOR and that belongs to the mTORC1 and mTORC2 complexes. Deptor is capable of inhibiting the kinase activity of mTOR. It is well known that the mTOR pathway is involved in various signaling pathways that are involved with various biological processes such as cell growth, apoptosis, autophagy, and the ER stress response. Therefore, Deptor, being a natural inhibitor of mTOR, has become very important in its study. Because of this, it is important to research its role regarding the development and progression of human malignancies, especially in hematologic malignancies. Due to its variation in expression in cancer, it has been suggested that Deptor can act as an oncogene or tumor suppressor depending on the cellular or tissue context. This review discusses recent advances in its transcriptional and post-transcriptional regulation of Deptor. As well as the advances regarding the activities of Deptor in hematological malignancies, its possible role as a biomarker, and its possible clinical relevance in these malignancies.
Collapse
Affiliation(s)
- Mario Morales-Martinez
- Molecular Signal Pathway in Cancer Laboratory, UIMEO, Oncology Hospital, Siglo XXI National Medical Center, IMSS, México City, México
| | - Alan Lichtenstein
- Department of Medicine, Hematology-Oncology Division, Greater Los Angeles VA Healthcare Center, UCLA Medical Center, Jonsson Comprehensive Cancer Center, Los Angeles, CA 90024, USA
| | - Mario I. Vega
- Molecular Signal Pathway in Cancer Laboratory, UIMEO, Oncology Hospital, Siglo XXI National Medical Center, IMSS, México City, México
- Department of Medicine, Hematology-Oncology Division, Greater Los Angeles VA Healthcare Center, UCLA Medical Center, Jonsson Comprehensive Cancer Center, Los Angeles, CA 90024, USA
| |
Collapse
|
|
32
|
Warnat-Herresthal S, Oestreich M, Schultze JL, Becker M. Artificial Intelligence in Blood Transcriptomics. Artif Intell Med 2021. [DOI: 10.1007/978-3-030-58080-3_262-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
|
|
33
|
Sharma N, Speed MC, Allen CP, Maranon DG, Williamson E, Singh S, Hromas R, Nickoloff JA. Distinct roles of structure-specific endonucleases EEPD1 and Metnase in replication stress responses. NAR Cancer 2020; 2:zcaa008. [PMID: 32743552 PMCID: PMC7380491 DOI: 10.1093/narcan/zcaa008] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2019] [Revised: 05/20/2020] [Accepted: 05/31/2020] [Indexed: 12/16/2022] Open
Abstract
Accurate DNA replication and segregation are critical for maintaining genome integrity and suppressing cancer. Metnase and EEPD1 are DNA damage response (DDR) proteins frequently dysregulated in cancer and implicated in cancer etiology and tumor response to genotoxic chemo- and radiotherapy. Here, we examine the DDR in human cell lines with CRISPR/Cas9 knockout of Metnase or EEPD1. The knockout cell lines exhibit slightly slower growth rates, significant hypersensitivity to replication stress, increased genome instability and distinct alterations in DDR signaling. Metnase and EEPD1 are structure-specific nucleases. EEPD1 is recruited to and cleaves stalled forks to initiate fork restart by homologous recombination. Here, we demonstrate that Metnase is also recruited to stalled forks where it appears to dimethylate histone H3 lysine 36 (H3K36me2), raising the possibility that H3K36me2 promotes DDR factor recruitment or limits nucleosome eviction to protect forks from nucleolytic attack. We show that stalled forks are cleaved normally in the absence of Metnase, an important and novel result because a prior study indicated that Metnase nuclease is important for timely fork restart. A double knockout was as sensitive to etoposide as either single knockout, suggesting a degree of epistasis between Metnase and EEPD1. We propose that EEPD1 initiates fork restart by cleaving stalled forks, and that Metnase may promote fork restart by processing homologous recombination intermediates and/or inducing H3K36me2 to recruit DDR factors. By accelerating fork restart, Metnase and EEPD1 reduce the chance that stalled replication forks will adopt toxic or genome-destabilizing structures, preventing genome instability and cancer. Metnase and EEPD1 are overexpressed in some cancers and thus may also promote resistance to genotoxic therapeutics.
Collapse
Affiliation(s)
- Neelam Sharma
- Department of Environmental and Radiological Health Sciences, Colorado State University, 1618 Campus Delivery, Fort Collins, CO 80523-1618, USA
| | - Michael C Speed
- Department of Environmental and Radiological Health Sciences, Colorado State University, 1618 Campus Delivery, Fort Collins, CO 80523-1618, USA
| | - Christopher P Allen
- Department of Microbiology, Immunology, and Pathology, Colorado State University, 1601Campus Delivery, Fort Collins, CO 80523-1601, USA
| | - David G Maranon
- Department of Environmental and Radiological Health Sciences, Colorado State University, 1618 Campus Delivery, Fort Collins, CO 80523-1618, USA
| | - Elizabeth Williamson
- Division of Hematology and Medical Oncology, Department of Medicine, University of Texas HealthScience Center, 7703 Floyd Curl Drive, San Antonio, TX 78229, USA
| | - Sudha Singh
- Division of Hematology and Medical Oncology, Department of Medicine, University of Texas HealthScience Center, 7703 Floyd Curl Drive, San Antonio, TX 78229, USA
| | - Robert Hromas
- Division of Hematology and Medical Oncology, Department of Medicine, University of Texas HealthScience Center, 7703 Floyd Curl Drive, San Antonio, TX 78229, USA
| | - Jac A Nickoloff
- Department of Environmental and Radiological Health Sciences, Colorado State University, 1618 Campus Delivery, Fort Collins, CO 80523-1618, USA
| |
Collapse
|
|
34
|
Fernandes MT, Calado SM, Mendes-Silva L, Bragança J. CITED2 and the modulation of the hypoxic response in cancer. World J Clin Oncol 2020; 11:260-274. [PMID: 32728529 PMCID: PMC7360518 DOI: 10.5306/wjco.v11.i5.260] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2020] [Revised: 04/13/2020] [Accepted: 05/12/2020] [Indexed: 02/06/2023] Open
Abstract
CITED2 (CBP/p300-interacting transactivator with Glu/Asp-rich C-terminal domain, 2) is a ubiquitously expressed protein exhibiting a high affinity for the CH1 domain of the transcriptional co-activators CBP/p300, for which it competes with hypoxia-inducible factors (HIFs). CITED2 is particularly efficient in the inhibition of HIF-1α-dependent transcription in different contexts, ranging from organ development and metabolic homeostasis to tissue regeneration and immunity, being also potentially involved in various other physiological processes. In addition, CITED2 plays an important role in inhibiting HIF in some diseases, including kidney and heart diseases and type 2-diabetes. In the particular case of cancer, CITED2 either functions by promoting or suppressing cancer development depending on the context and type of tumors. For instance, CITED2 overexpression promotes breast and prostate cancers, as well as acute myeloid leukemia, while its expression is downregulated to sustain colorectal cancer and hepatocellular carcinoma. In addition, the role of CITED2 in the maintenance of cancer stem cells reveals its potential as a target in non-small cell lung carcinoma and acute myeloid leukemia, for example. But besides the wide body of evidence linking both CITED2 and HIF signaling to carcinogenesis, little data is available regarding CITED2 role as a negative regulator of HIF-1α specifically in cancer. Therefore, comprehensive studies exploring further the interactions of these two important mediators in cancer-specific models are sorely needed and this can potentially lead to the development of novel targeted therapies.
Collapse
Affiliation(s)
- Mónica T Fernandes
- School of Health, Universidade do Algarve, Campus of Gambelas, Faro 8005-139, Portugal
- Centre for Biomedical Research, Universidade do Algarve, Campus of Gambelas, Faro 8005-139, Portugal
- Algarve Biomedical Centre, Faro 8005-139, Portugal
| | - Sofia M Calado
- Centre for Biomedical Research, Universidade do Algarve, Campus of Gambelas, Faro 8005-139, Portugal
- Algarve Biomedical Centre, Faro 8005-139, Portugal
| | - Leonardo Mendes-Silva
- Centre for Biomedical Research, Universidade do Algarve, Campus of Gambelas, Faro 8005-139, Portugal
- Algarve Biomedical Centre, Faro 8005-139, Portugal
- Department of Biomedical Sciences and Medicine, Universidade do Algarve, Campus of Gambelas, Faro 8005-139, Portugal
| | - José Bragança
- Centre for Biomedical Research, Universidade do Algarve, Campus of Gambelas, Faro 8005-139, Portugal
- Algarve Biomedical Centre, Faro 8005-139, Portugal
- Department of Biomedical Sciences and Medicine, Universidade do Algarve, Campus of Gambelas, Faro 8005-139, Portugal
| |
Collapse
|
|
35
|
Zhang T, Yang J, Vaikari VP, Beckford JS, Wu S, Akhtari M, Alachkar H. Apolipoprotein C2 - CD36 Promotes Leukemia Growth and Presents a Targetable Axis in Acute Myeloid Leukemia. Blood Cancer Discov 2020; 1:198-213. [PMID: 32944714 DOI: 10.1158/2643-3230.bcd-19-0077] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
Acute myeloid leukemia (AML) is a devastating hematologic malignancy that affects the hematopoietic stem cells. The 5-year overall survival (OS) of patients with AML is less than 30%, highlighting the urgent need to identify new therapeutic targets. Here, we analyze gene expression datasets for genes that are differentially overexpressed in AML cells compared with healthy hematopoietic cells. We report that apolipoprotein C2 (APOC2) mRNA is significantly overexpressed in AML, particularly in patients with mixed-lineage leukemia rearrangements. By multivariate analysis, high APOC2 expression in leukemia blasts is significantly associated with decreased OS (HR: 2.51; 95% CI, 1.03-6.07; P = 0.04). APOC2 is a small secreted apolipoprotein that constitutes chylomicrons, very-low-density lipoproteins, and high-density lipoproteins with other apolipoproteins. APOC2 activates lipoprotein lipase and contributes to lipid metabolism. By gain and loss of function approaches in cultured AML cells, we demonstrate that APOC2 promotes leukemia growth via CD36-mediated LYN-ERK signaling activation. Knockdown or pharmacological inhibition of either APOC2 or CD36 reduces cell proliferation, induces apoptosis in vitro, and delays leukemia progression in mice. Altogether, this study establishes APOC2-CD36 axis as a potential therapeutic target in AML.
Collapse
Affiliation(s)
- Tian Zhang
- Keck School of Medicine, University of Southern California, Los Angeles, California
| | - Jiawen Yang
- Titus Family Department of Clinical Pharmacy, School of Pharmacy, University of Southern California, Los Angeles, California
| | - Vijaya P Vaikari
- Titus Family Department of Clinical Pharmacy, School of Pharmacy, University of Southern California, Los Angeles, California
| | - John S Beckford
- Titus Family Department of Clinical Pharmacy, School of Pharmacy, University of Southern California, Los Angeles, California
| | - Sharon Wu
- Titus Family Department of Clinical Pharmacy, School of Pharmacy, University of Southern California, Los Angeles, California
| | - Mojtaba Akhtari
- Keck School of Medicine, University of Southern California, Los Angeles, California.,Loma Linda University Cancer Center, Loma Linda University, Loma Linda, California.,USC Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California
| | - Houda Alachkar
- Titus Family Department of Clinical Pharmacy, School of Pharmacy, University of Southern California, Los Angeles, California.,USC Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California
| |
Collapse
|
|
36
|
Wang Y, Liu Y, Zhou C, Wang C, Zhang N, Cao D, Li Q, Wang Z. An AKR1C3-specific prodrug with potent anti-tumor activities against T-ALL. Leuk Lymphoma 2020; 61:1660-1668. [PMID: 32091283 DOI: 10.1080/10428194.2020.1728746] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Affiliation(s)
- Yanlan Wang
- School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, China
| | - Yue Liu
- School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, China
| | - Changhua Zhou
- School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, China
| | - Chunnian Wang
- School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, China
| | - Ning Zhang
- Department of Urology, Peking University Cancer Hospital, Beijing Institute for Cancer Research, Beijing, China
| | - Donglin Cao
- Department of Laboratory Medicine, Guangdong Second Provincial General Hospital, Guangzhou, China
| | - Qing Li
- School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, China
| | - Zhong Wang
- School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, China
| |
Collapse
|
|
37
|
Cao Y, Liu Y, Shang L, Wei W, Shen Y, Gu Q, Xie X, Dong W, Lin Y, Yue Y, Wang F, Gu W. Decitabine and all-trans retinoic acid synergistically exhibit cytotoxicity against elderly AML patients via miR-34a/MYCN axis. Biomed Pharmacother 2020; 125:109878. [PMID: 32006898 DOI: 10.1016/j.biopha.2020.109878] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2019] [Revised: 01/15/2020] [Accepted: 01/17/2020] [Indexed: 12/16/2022] Open
Abstract
This study aimed to investigate the efficacy and mechanism of decitabine (DAC) and all-trans retinoic acid (ATRA) in elderly acute myeloid leukemia (AML) patients and cultured cells. Our clinical trial enrolled 36 elderly patients who were judged ineligible for conventional chemotherapy, receiving DAC and ATRA regimen (DAC 20 mg/m2 days 1-5; ATRA 20 mg/m2 days 4-28 in the first cycle and days 1-28 in the subsequent cycle). Treated with a median of 3 cycles (range 1-6), 44.4 % of patients achieved complete remission (CR), 11.1 % achieved CR with incomplete peripheral count recovery (CRi) and 13.9 % achieved partial remission (PR). The median overall survival (OS) was 12.1 months; the 1-year and 2-year OS rates were 49.6 % and 17.2 %. In addition, our in vitro studies indicated that the antineoplastic activities of DAC and ATRA mutually reinforced, which induced growth inhibition, cell cycle arrest and apoptosis of AML cells. Meanwhile, we found DAC and ATRA inhibited DNMT1, activated miR-34a via promoter hypomethylation, down-regulated its target MYCN and thus exerted a synergistic antineoplastic effect. In conclusion, DAC plus ATRA regimen might be effective and well-tolerated for elderly patients partially through modulating miR-34a/MYCN axis.
Collapse
Affiliation(s)
- Yang Cao
- Department of Hematology, The Third Affiliated Hospital of Soochow University, The First People's Hospital of Changzhou, Jiangsu Province, 213003, PR China
| | - Yue Liu
- Department of Hematology, The Third Affiliated Hospital of Soochow University, The First People's Hospital of Changzhou, Jiangsu Province, 213003, PR China
| | - Limei Shang
- Department of Hematology, The Third Affiliated Hospital of Soochow University, The First People's Hospital of Changzhou, Jiangsu Province, 213003, PR China
| | - Wei Wei
- Department of Hematology, The Third Affiliated Hospital of Soochow University, The First People's Hospital of Changzhou, Jiangsu Province, 213003, PR China
| | - Yangling Shen
- Department of Hematology, The Third Affiliated Hospital of Soochow University, The First People's Hospital of Changzhou, Jiangsu Province, 213003, PR China
| | - Quan Gu
- Department of Hematology, The Third Affiliated Hospital of Soochow University, The First People's Hospital of Changzhou, Jiangsu Province, 213003, PR China
| | - Xiaobao Xie
- Department of Hematology, The Third Affiliated Hospital of Soochow University, The First People's Hospital of Changzhou, Jiangsu Province, 213003, PR China
| | - Weimin Dong
- Department of Hematology, The Third Affiliated Hospital of Soochow University, The First People's Hospital of Changzhou, Jiangsu Province, 213003, PR China
| | - Yan Lin
- Department of Hematology, The Third Affiliated Hospital of Soochow University, The First People's Hospital of Changzhou, Jiangsu Province, 213003, PR China
| | - Yanhua Yue
- Department of Hematology, The Third Affiliated Hospital of Soochow University, The First People's Hospital of Changzhou, Jiangsu Province, 213003, PR China
| | - Fei Wang
- Department of Hematology, The Third Affiliated Hospital of Soochow University, The First People's Hospital of Changzhou, Jiangsu Province, 213003, PR China
| | - Weiying Gu
- Department of Hematology, The Third Affiliated Hospital of Soochow University, The First People's Hospital of Changzhou, Jiangsu Province, 213003, PR China.
| |
Collapse
|
|
38
|
Scalable Prediction of Acute Myeloid Leukemia Using High-Dimensional Machine Learning and Blood Transcriptomics. iScience 2019; 23:100780. [PMID: 31918046 PMCID: PMC6992905 DOI: 10.1016/j.isci.2019.100780] [Citation(s) in RCA: 52] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2019] [Revised: 12/03/2019] [Accepted: 12/12/2019] [Indexed: 01/16/2023] Open
Abstract
Acute myeloid leukemia (AML) is a severe, mostly fatal hematopoietic malignancy. We were interested in whether transcriptomic-based machine learning could predict AML status without requiring expert input. Using 12,029 samples from 105 different studies, we present a large-scale study of machine learning-based prediction of AML in which we address key questions relating to the combination of machine learning and transcriptomics and their practical use. We find data-driven, high-dimensional approaches—in which multivariate signatures are learned directly from genome-wide data with no prior knowledge—to be accurate and robust. Importantly, these approaches are highly scalable with low marginal cost, essentially matching human expert annotation in a near-automated workflow. Our results support the notion that transcriptomics combined with machine learning could be used as part of an integrated -omics approach wherein risk prediction, differential diagnosis, and subclassification of AML are achieved by genomics while diagnosis could be assisted by transcriptomic-based machine learning.
Study presents one of the largest transcriptomics datasets to date for AML prediction Effective classifiers can be obtained by high-dimensional machine learning Accuracy increases with dataset size Includes challenging scenarios such as cross-study and cross-technology
Collapse
|
|
39
|
Gokhale S, Lu W, Zhu S, Liu Y, Hart RP, Rabinowitz JD, Xie P. Elevated Choline Kinase α-Mediated Choline Metabolism Supports the Prolonged Survival of TRAF3-Deficient B Lymphocytes. THE JOURNAL OF IMMUNOLOGY 2019; 204:459-471. [PMID: 31826940 DOI: 10.4049/jimmunol.1900658] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/12/2019] [Accepted: 11/13/2019] [Indexed: 12/27/2022]
Abstract
Specific deletion of the tumor suppressor TRAF3 from B lymphocytes in mice leads to the prolonged survival of mature B cells and expanded B cell compartments in secondary lymphoid organs. In the current study, we investigated the metabolic basis of TRAF3-mediated regulation of B cell survival by employing metabolomic, lipidomic, and transcriptomic analyses. We compared the polar metabolites, lipids, and metabolic enzymes of resting splenic B cells purified from young adult B cell-specific Traf3 -/- and littermate control mice. We found that multiple metabolites, lipids, and enzymes regulated by TRAF3 in B cells are clustered in the choline metabolic pathway. Using stable isotope labeling, we demonstrated that phosphocholine and phosphatidylcholine biosynthesis was markedly elevated in Traf3 -/- mouse B cells and decreased in TRAF3-reconstituted human multiple myeloma cells. Furthermore, pharmacological inhibition of choline kinase α, an enzyme that catalyzes phosphocholine synthesis and was strikingly increased in Traf3 -/- B cells, substantially reversed the survival phenotype of Traf3 -/- B cells both in vitro and in vivo. Taken together, our results indicate that enhanced phosphocholine and phosphatidylcholine synthesis supports the prolonged survival of Traf3 -/- B lymphocytes. Our findings suggest that TRAF3-regulated choline metabolism has diagnostic and therapeutic value for B cell malignancies with TRAF3 deletions or relevant mutations.
Collapse
Affiliation(s)
- Samantha Gokhale
- Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, NJ 08854.,Graduate Program in Cellular and Molecular Pharmacology, Rutgers University, Piscataway, NJ 08854
| | - Wenyun Lu
- Department of Chemistry, Princeton University, Princeton, NJ 08544.,Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ 08544.,Rutgers Cancer Institute of New Jersey, New Brunswick, NJ 08901; and
| | - Sining Zhu
- Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, NJ 08854.,Graduate Program in Cellular and Molecular Pharmacology, Rutgers University, Piscataway, NJ 08854
| | - Yingying Liu
- Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, NJ 08854
| | - Ronald P Hart
- Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, NJ 08854.,Rutgers Cancer Institute of New Jersey, New Brunswick, NJ 08901; and.,W.M. Keck Center for Collaborative Neuroscience, Rutgers University, Piscataway, NJ 08854
| | - Joshua D Rabinowitz
- Department of Chemistry, Princeton University, Princeton, NJ 08544.,Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ 08544.,Rutgers Cancer Institute of New Jersey, New Brunswick, NJ 08901; and
| | - Ping Xie
- Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, NJ 08854; .,Rutgers Cancer Institute of New Jersey, New Brunswick, NJ 08901; and
| |
Collapse
|
|
40
|
Yao Y, Su J, Zhao L, Li R, Liu K, Wang S. CHCHD2 promotes hepatocellular carcinoma and indicates poor prognosis of hepatocellular carcinoma patients. J Cancer 2019; 10:6822-6828. [PMID: 31839816 PMCID: PMC6909951 DOI: 10.7150/jca.31158] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2018] [Accepted: 08/29/2019] [Indexed: 01/22/2023] Open
Abstract
The coiled-coil-helix-coiled-coil-helix domain containing 2 (CHCHD2) is overexpressed in several types of cancer. This study aimed to investigate the role of CHCHD2 in hepatocellular carcinoma (HCC). The expression of CHCHD2 in HCC and non-tumorous tissues was detected by immunohistochemistry and Western blot analysis, and the correlation between CHCHD2 expression and clinicopathological features of HCC was analyzed. Furthermore, the proliferation, apoptosis and migration of HepG2 cells with CHCHD2 knockdown were examined. We found that CHCHD2 was upregulated in HCC tissues, and high CHCHD2 expression was associated with poor differentiation, lymph node metastasis, local tissue invasion, high TNM grade of HCC and poor patient survival. Depletion of CHCHD2 led to significantly reduced cell proliferation, increased apoptosis and diminished migratory capacity in HepG2 cells. In addition, HCC tissues had high expression of CD105, a microvessel marker, and HepG2 cells depleted of CHCHD2 had low CD105 expression. In conclusion, CHCHD2 may play an oncogenic role in HCC via promoting tumor cell growth and migration while preventing apoptosis. CHCHD2 is a potential biomarker for poor outcome of HCC patients.
Collapse
Affiliation(s)
- Yang Yao
- Department of Central laboratory, The First Affiliated Hospital, Xi'an Medical University, Xi'an, Shaanxi 710077, PR China
| | - Jie Su
- Department of Central laboratory, The First Affiliated Hospital, Xi'an Medical University, Xi'an, Shaanxi 710077, PR China
| | - Lei Zhao
- Department of Molecular Physiology and Biophysics, Holden Comprehensive Cancer Center, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA
| | - Rong Li
- Department of Ophthalmology, The First Affiliated Hospital of Xi'an Medical University, Xi'an, Shaanxi 710077, PR China
| | - Kaige Liu
- Department of Gastroenterology, the First Affiliated Hospital, Xi'an Medical University, Xi'an, Shaanxi 710077, PR China
| | - Shengyu Wang
- Department of Pulmonary and Critical Care Medicine, The First Affiliated Hospital of Xi'an Medical University, Xi'an, Shaanxi, 710077, China
| |
Collapse
|
|
41
|
Yang J, Wu S, Alachkar H. Characterization of upregulated adhesion GPCRs in acute myeloid leukemia. Transl Res 2019; 212:26-35. [PMID: 31153896 PMCID: PMC7473775 DOI: 10.1016/j.trsl.2019.05.004] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/12/2018] [Revised: 05/14/2019] [Accepted: 05/16/2019] [Indexed: 11/20/2022]
Abstract
The role of adhesion G protein-coupled receptors (aGPCRs) in cancer has become increasingly evident in recent years. Yet, data supporting the contribution of this family of genes to hematological malignancies, particularly acute myeloid leukemia (AML) are limited. Here, we use publicly available genomic data to characterize the expression of the 33 aGPCRs in patients with AML and examine whether upregulation of these genes is associated with the clinical and molecular characteristics of patients. Upregulation in one or more of eight aGPCR genes (ADGRB1, ADGRC2, ADGRD1, ADGRE1, ADGRE2, ADGRE5, ADGRG1, and/or ADGRG3) was significantly associated with shorter overall survival (OS) (median OS: 11.8 vs 55.4 months; P < 0.0001). This was also significant in multivariate survival analysis (hazard ratio: 1.73; 95% confidence interval 1.11-2.69; P = 0.015) after adjusting for age, molecular risk status, and transplant status. High expression of the eight aGPCRs was significantly associated with older age (≥60; P = 0.011). Patients with high aGPCRs expression were more frequently classified in the poor molecular risk status group and less in the good risk status group compared with patients with low aGPCRs expression (31% vs 17% P = 0.049 and 14% vs 28% P = 0.027, respectively). Via Ingenuity Pathway Analysis, we identified the interleukin-8 signaling pathway among the most activated pathways in patients with high aGPCRs expression. Overall, our data suggest that particular aGPCRs are frequently upregulated in AML and associated with poor clinical outcome. Future functional and mechanistic analyses are needed to address the role of aGPCRs in AML.
Collapse
Affiliation(s)
- Jiawen Yang
- Department of Clinical Pharmacy, USC School of Pharmacy, University of Southern California, Los Angeles, California
| | - Sharon Wu
- Department of Clinical Pharmacy, USC School of Pharmacy, University of Southern California, Los Angeles, California
| | - Houda Alachkar
- Department of Clinical Pharmacy, USC School of Pharmacy, University of Southern California, Los Angeles, California.
| |
Collapse
|
|
42
|
Rajendran A, Vaidya K, Mendoza J, Bridwell-Rabb J, Kamat SS. Functional Annotation of ABHD14B, an Orphan Serine Hydrolase Enzyme. Biochemistry 2019; 59:183-196. [PMID: 31478652 DOI: 10.1021/acs.biochem.9b00703] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
The metabolic serine hydrolase family is, arguably, one of the largest functional enzyme classes in mammals, including humans, comprising 1-2% of the total proteome. This enzyme family uses a conserved nucleophilic serine residue in the active site to perform diverse hydrolytic reactions and consists of proteases, lipases, esterases, amidases, and transacylases, which are prototypical members of this family. In humans, this enzyme family consists of >250, of which approximately 40% members remain unannotated, in terms of both their endogenous substrates and the biological pathways that they regulate. The enzyme ABHD14B, an outlying member of this family, is also known as CCG1/TAFII250-interacting factor B, as it was found to be associated with transcription initiation factor TFIID. The crystal structure of human ABHD14B was determined more than a decade ago; however, its endogenous substrates remain elusive. In this paper, we annotate ABHD14B as a lysine deacetylase (KDAC), showing this enzyme's ability to transfer an acetyl group from a post-translationally acetylated lysine to coenzyme A (CoA), to yield acetyl-CoA, while regenerating the free amine of protein lysine residues. We validate these findings by in vitro biochemical assays using recombinantly purified human ABHD14B in conjunction with cellular studies in a mammalian cell line by knocking down ABHD14B and by identification of a putative substrate binding site. Finally, we report the development and characterization of a much-needed, exquisitely selective ABHD14B antibody, and using it, we map the cellular and tissue distribution of ABHD14B and prospective metabolic pathways that this enzyme might biologically regulate.
Collapse
Affiliation(s)
- Abinaya Rajendran
- Department of Biology , Indian Institute of Science Education and Research (IISER) Pune , Dr. Homi Bhabha Road Pashan , Pune 411008 , Maharashtra , India
| | - Kaveri Vaidya
- Department of Biology , Indian Institute of Science Education and Research (IISER) Pune , Dr. Homi Bhabha Road Pashan , Pune 411008 , Maharashtra , India
| | - Johnny Mendoza
- Department of Chemistry, College of Literature, Science and the Arts , University of Michigan , Ann Arbor , Michigan 48109 , United States
| | - Jennifer Bridwell-Rabb
- Department of Chemistry, College of Literature, Science and the Arts , University of Michigan , Ann Arbor , Michigan 48109 , United States
| | - Siddhesh S Kamat
- Department of Biology , Indian Institute of Science Education and Research (IISER) Pune , Dr. Homi Bhabha Road Pashan , Pune 411008 , Maharashtra , India
| |
Collapse
|
|
43
|
Moreno CS. SOX4: The unappreciated oncogene. Semin Cancer Biol 2019; 67:57-64. [PMID: 31445218 DOI: 10.1016/j.semcancer.2019.08.027] [Citation(s) in RCA: 142] [Impact Index Per Article: 23.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2019] [Revised: 07/31/2019] [Accepted: 08/20/2019] [Indexed: 01/10/2023]
Abstract
SOX4 is an essential developmental transcription factor that regulates stemness, differentiation, progenitor development, and multiple developmental pathways including PI3K, Wnt, and TGFβ signaling. The SOX4 gene is frequently amplified and overexpressed in over 20 types of malignancies, and multiple lines of evidence support that notion that SOX4 is an oncogene. Its overexpression is due to both gene amplification and to activation of PI3K, Wnt, and TGFβ pathways that SOX4 regulates. SOX4 interacts with multiple other transcription factors, rendering many of its impacts on gene expression context and tissue-specific. Nevertheless, there are common themes that run through many of the effects of SOX4 hyperactivity, such as the promotion of cell survival, stemness, the epithelial to mesenchymal transition, migration, and metastasis. Specific targeting of SOX4 remains a challenge for future cancer research and drug development.
Collapse
Affiliation(s)
- Carlos S Moreno
- Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Whitehead Bldg, Rm 105J, 615 Michael St. Atlanta, GA, USA.
| |
Collapse
|
|
44
|
The Role of the HOXA Gene Family in Acute Myeloid Leukemia. Genes (Basel) 2019; 10:genes10080621. [PMID: 31426381 PMCID: PMC6723066 DOI: 10.3390/genes10080621] [Citation(s) in RCA: 50] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2019] [Revised: 08/06/2019] [Accepted: 08/14/2019] [Indexed: 01/12/2023] Open
Abstract
The HOXA gene family is associated with various cancer types. However, the role of HOXA genes in acute myeloid leukemia (AML) have not been comprehensively studied. We compared the transcriptional expression, survival data, and network analysis of HOXA-associated signaling pathways in patients with AML using the ONCOMINE, GEPIA, LinkedOmics, cBioPortal, and Metascape databases. We observed that HOXA2-10 mRNA expression levels were significantly upregulated in AML and that high HOXA1-10 expression was associated with poor AML patient prognosis. The HOXA genes were altered in ~18% of the AML samples, either in terms of amplification, deep deletion, or elevated mRNA expression. The following pathways were modulated by HOXA gene upregulation: GO:0048706: embryonic skeletal system development; R-HSA-5617472: activation of HOX genes in anterior hindbrain development during early embryogenesis; GO:0060216: definitive hemopoiesis; hsa05202: transcriptional mis-regulation in cancer; and GO:0045638: negative regulation of myeloid cell differentiation, and they were significantly regulated due to alterations affecting the HOXA genes. This study identified HOXA3-10 genes as potential AML therapeutic targets and prognostic markers.
Collapse
|
|
45
|
Vaikari VP, Du Y, Wu S, Zhang T, Metzeler K, Batcha AMN, Herold T, Hiddemann W, Akhtari M, Alachkar H. Clinical and preclinical characterization of CD99 isoforms in acute myeloid leukemia. Haematologica 2019; 105:999-1012. [PMID: 31371417 PMCID: PMC7109747 DOI: 10.3324/haematol.2018.207001] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2018] [Accepted: 07/25/2019] [Indexed: 12/19/2022] Open
Abstract
In an effort to identify target genes in acute myeloid leukemia (AML), we compared gene expression profiles between normal and AML cells from various publicly available datasets. We identified CD99, a gene that is up-regulated in AML patients. In 186 patients from The Cancer Genome Atlas AML dataset, CD99 was over-expressed in patients with FLT3-ITD and was down-regulated in patients with TP53 mutations. CD99 is a trans-membrane protein expressed on leukocytes and plays a role in cell adhesion, trans-endothelial migration, and T-cell differentiation. The CD99 gene encodes two isoforms with distinct expression and functional profiles in both normal and malignant tissues. Here we report that, although the CD99 long isoform initially induces an increase in cell proliferation, it also induces higher levels of reactive oxygen species, DNA damage, apoptosis and a subsequent decrease in cell viability. In several leukemia murine models, the CD99 long isoform delayed disease progression and resulted in lower leukemia engraftment in the bone marrow. Furthermore, the CD99 monoclonal antibody reduced cell viability, colony formation, and cell migration, and induced cell differentiation and apoptosis in leukemia cell lines and primary blasts. Mechanistically, CD99 long isoform resulted in transient induction followed by a dramatic decrease in both ERK and SRC phosphorylation. Altogether, our study provides new insights into the role of CD99 isoforms in AML that could potentially be relevant for the preclinical development of CD99 targeted therapy.
Collapse
Affiliation(s)
- Vijaya Pooja Vaikari
- Titus Family Department of Clinical Pharmacy, School of Pharmacy, University of Southern California, Los Angeles, CA, USA
| | - Yang Du
- Titus Family Department of Clinical Pharmacy, School of Pharmacy, University of Southern California, Los Angeles, CA, USA
| | - Sharon Wu
- Titus Family Department of Clinical Pharmacy, School of Pharmacy, University of Southern California, Los Angeles, CA, USA
| | - Tian Zhang
- Medical Biology Program, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Klaus Metzeler
- Laboratory for Leukemia Diagnostics, Department of Medicine III, University Hospital, LMU Munich, Munich, Germany
| | - Aarif M N Batcha
- Institute of Medical Data Processing, Biometrics and Epidemiology (IBE), Faculty of Medicine, LMU Munich, Munich, Germany.,Data Integration for Future Medicine (DiFuture, www.difuture.de), LMU Munich, Germany
| | - Tobias Herold
- Laboratory for Leukemia Diagnostics, Department of Medicine III, University Hospital, LMU Munich, Munich, Germany.,Research Unit Apoptosis in Hematopoietic Stem Cells, Helmholtz Zentrum München, German Center for Environmental Health (HMGU), Munich Germany
| | - Wolfgang Hiddemann
- Laboratory for Leukemia Diagnostics, Department of Medicine III, University Hospital, LMU Munich, Munich, Germany
| | - Mojtaba Akhtari
- USC Norris Comprehensive Cancer Center, University of Southern California, Los Angeles Southern California, Los Angeles, CA, USA
| | - Houda Alachkar
- Titus Family Department of Clinical Pharmacy, School of Pharmacy, University of Southern California, Los Angeles, CA, USA .,USC Norris Comprehensive Cancer Center, University of Southern California, Los Angeles Southern California, Los Angeles, CA, USA
| |
Collapse
|
|
46
|
Wu S, Fahmy N, Alachkar H. The mitochondrial transcription machinery genes are upregulated in acute myeloid leukemia and associated with poor clinical outcome. Metabol Open 2019; 2:100009. [PMID: 32812906 PMCID: PMC7424792 DOI: 10.1016/j.metop.2019.100009] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2019] [Revised: 04/12/2019] [Accepted: 04/25/2019] [Indexed: 12/27/2022] Open
Abstract
BACKGROUND Acute myeloid leukemia (AML) is characterized by rapid growth of abnormal blasts that overcrowd normal hematopoiesis. Defective mitochondrial biogenesis has been implicated in AML, which we believe is partly due to the deregulation of the mitochondrial transcription machinery (MTM) genes influencing the expression of mitochondrial genes. Here, we aim to characterize MTM gene upregulation in AML. METHODS Molecular and clinical patient data were retrieved from several public AML datasets. Kaplan-Meier survival curves were used to compare overall survival between patients, while Mann-Whitney U's non-parametric and Fisher's exact test were used for comparing continuous and categorical variables, respectively. RESULTS The MTM genes TFB1M, TFB2M, TFAM, and POLRMT were upregulated in patients with AML compared with healthy donors. Upregulation of one or more of these genes was associated with higher percentage of peripheral blood blasts (P = 0.002), normal cytogenetic status (P = 0.027) and NPM1 mutations (P = 0.009). Additionally, patients with high expression of MTM genes (Z ≥ 1) had shorter median overall survival compared with low MTM gene expression (Z < 1) (months: 11.8 vs 24.1, P = 0.027; multivariate survival analysis Cox Proportional Hazards model, HR: 1.82 (1.22-2.70); p-value: 0.003). CONCLUSION The mitochondrial transcriptional machinery is upregulated and associated with worse clinical outcome in patients with AML and may present a viable therapeutic target.
Collapse
Affiliation(s)
- Sharon Wu
- USC School of Pharmacy, University of Southern California, Los Angeles, CA, USA
| | - Nicole Fahmy
- USC School of Pharmacy, University of Southern California, Los Angeles, CA, USA
| | - Houda Alachkar
- USC School of Pharmacy, University of Southern California, Los Angeles, CA, USA
- USC Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, USA
| |
Collapse
|
|
47
|
Post JB, Hami N, Mertens AEE, Elfrink S, Bos JL, Snippert HJG. CRISPR-induced RASGAP deficiencies in colorectal cancer organoids reveal that only loss of NF1 promotes resistance to EGFR inhibition. Oncotarget 2019; 10:1440-1457. [PMID: 30858928 PMCID: PMC6402720 DOI: 10.18632/oncotarget.26677] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2018] [Accepted: 02/01/2019] [Indexed: 12/16/2022] Open
Abstract
Anti-EGFR therapy is used to treat metastatic colorectal cancer (CRC) patients, for which initial response rates of 10-20% have been achieved. Although the presence of HER2 amplifications and oncogenic mutations in KRAS, NRAS, and BRAF are associated with EGFR-targeted therapy resistance, for a large population of CRC patients the underlying mechanism of RAS-MEK-ERK hyperactivation is not clear. Loss-of-function mutations in RASGAPs are often speculated in literature to promote CRC growth as being negative regulators of RAS, but direct experimental evidence is lacking. We generated a CRISPR-mediated knock out panel of all RASGAPs in patient-derived CRC organoids and found that only loss of NF1, but no other RASGAPs e.g. RASA1, results in enhanced RAS-ERK signal amplification and improved tolerance towards limited EGF stimulation. Our data suggests that NF1-deficient CRCs are likely not responsive to anti-EGFR monotherapy and can potentially function as a biomarker for CRC progression.
Collapse
Affiliation(s)
- Jasmin B Post
- Center for Molecular Medicine, Section Molecular Cancer Research, University Medical Center Utrecht, Utrecht, The Netherlands.,Oncode Netherlands, Institute Netherlands, Office Jaarbeurs Innovation Mile, Utrecht, The Netherlands
| | - Nizar Hami
- Center for Molecular Medicine, Section Molecular Cancer Research, University Medical Center Utrecht, Utrecht, The Netherlands.,Oncode Netherlands, Institute Netherlands, Office Jaarbeurs Innovation Mile, Utrecht, The Netherlands
| | - Alexander E E Mertens
- Center for Molecular Medicine, Section Molecular Cancer Research, University Medical Center Utrecht, Utrecht, The Netherlands.,Oncode Netherlands, Institute Netherlands, Office Jaarbeurs Innovation Mile, Utrecht, The Netherlands
| | - Suraya Elfrink
- Center for Molecular Medicine, Section Molecular Cancer Research, University Medical Center Utrecht, Utrecht, The Netherlands.,Oncode Netherlands, Institute Netherlands, Office Jaarbeurs Innovation Mile, Utrecht, The Netherlands
| | - Johannes L Bos
- Center for Molecular Medicine, Section Molecular Cancer Research, University Medical Center Utrecht, Utrecht, The Netherlands.,Oncode Netherlands, Institute Netherlands, Office Jaarbeurs Innovation Mile, Utrecht, The Netherlands
| | - Hugo J G Snippert
- Center for Molecular Medicine, Section Molecular Cancer Research, University Medical Center Utrecht, Utrecht, The Netherlands.,Oncode Netherlands, Institute Netherlands, Office Jaarbeurs Innovation Mile, Utrecht, The Netherlands
| |
Collapse
|
|
48
|
Sun CC, Li SJ, Chen ZL, Li G, Zhang Q, Li DJ. Expression and Prognosis Analyses of Runt-Related Transcription Factor Family in Human Leukemia. MOLECULAR THERAPY-ONCOLYTICS 2018; 12:103-111. [PMID: 30719500 PMCID: PMC6350111 DOI: 10.1016/j.omto.2018.12.008] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/23/2018] [Accepted: 12/11/2018] [Indexed: 12/21/2022]
Abstract
Despite advances in early diagnosis and treatment, cancer remains the major reason for mortality worldwide. The Runt-related transcription factor (RUNX) family has been reported to participate in diverse human diseases. However, little is known about their expression and prognostic values in human leukemia. Herein, we conducted a detailed cancer versus normal analysis. The mRNA expression levels of the RUNX family in various kinds of cancers, including leukemia, were analyzed via the ONCOMINE and GEPIA (Gene Expression Profiling Interactive Analysis) databases. We observed that the mRNA expression levels of RUNX1, RUNX2, and RUNX3 were all increased in most cancers compared with normal tissues, especially in leukemia. Moreover, the expression levels of RUNX1, RUNX2, and RUNX3 are also highly expressed in almost all cancer cell lines, particularly in acute myeloid leukemia (AML) cell lines, analyzed by Cancer Cell Line Encyclopedia (CCLE) and European Bioinformatics Institute (EMBL-EBI) databases. Further, the LinkedOmics and GEPIA databases were used to evaluate the prognostic values. In survival analyses based on LinkedOmics, higher expression of RUNX1 and RUNX2 indicated a better overall survival (OS), but with no significance, whereas increased RUNX3 revealed a poor OS in leukemia. In addition, the GEPIA dataset was also used to perform survival analyses, and results manifested that the expression of RUNX1 and RUNX2 had no remarkable correction with OS in leukemia, but it showed highly expressed RUNX3 was significantly related with poor OS in leukemia. In conclusion, the RUNX family showed significant expression differences between cancer and normal tissues, especially leukemia, and RUNX3 could be a promising prognostic biomarker for leukemia.
Collapse
Affiliation(s)
- Cheng-Cao Sun
- Department of Preventive Medicine, School of Health Sciences, Wuhan University, Wuhan, Hubei 430071, P.R. China
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
- Corresponding author: Cheng-Cao Sun, Department of Preventive Medicine, School of Health Sciences, Wuhan University, No. 115 Donghu Road, Wuchang District, Wuhan, Hubei 430071, P.R. China.
| | - Shu-Jun Li
- Wuhan Hospital for the Prevention and Treatment of Occupational Diseases, Wuhan, Hubei 430022, P.R. China
| | - Zhen-Long Chen
- Wuhan Hospital for the Prevention and Treatment of Occupational Diseases, Wuhan, Hubei 430022, P.R. China
| | - Guang Li
- Department of Oncology, Wuhan Pu-Ai Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430034, P.R. China
| | - Qian Zhang
- Department of Pathology, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430014, P.R. China
| | - De-Jia Li
- Department of Preventive Medicine, School of Health Sciences, Wuhan University, Wuhan, Hubei 430071, P.R. China
- Corresponding author: De-Jia Li, Department of Preventive Medicine, School of Health Sciences, Wuhan University, No. 115 Donghu Road, Wuchang District, Wuhan, Hubei 430071, P.R. China.
| |
Collapse
|
|
49
|
Li JF, Dai YT, Lilljebjörn H, Shen SH, Cui BW, Bai L, Liu YF, Qian MX, Kubota Y, Kiyoi H, Matsumura I, Miyazaki Y, Olsson L, Tan AM, Ariffin H, Chen J, Takita J, Yasuda T, Mano H, Johansson B, Yang JJ, Yeoh AEJ, Hayakawa F, Chen Z, Pui CH, Fioretos T, Chen SJ, Huang JY. Transcriptional landscape of B cell precursor acute lymphoblastic leukemia based on an international study of 1,223 cases. Proc Natl Acad Sci U S A 2018; 115:E11711-E11720. [PMID: 30487223 PMCID: PMC6294900 DOI: 10.1073/pnas.1814397115] [Citation(s) in RCA: 203] [Impact Index Per Article: 29.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023] Open
Abstract
Most B cell precursor acute lymphoblastic leukemia (BCP ALL) can be classified into known major genetic subtypes, while a substantial proportion of BCP ALL remains poorly characterized in relation to its underlying genomic abnormalities. We therefore initiated a large-scale international study to reanalyze and delineate the transcriptome landscape of 1,223 BCP ALL cases using RNA sequencing. Fourteen BCP ALL gene expression subgroups (G1 to G14) were identified. Apart from extending eight previously described subgroups (G1 to G8 associated with MEF2D fusions, TCF3-PBX1 fusions, ETV6-RUNX1-positive/ETV6-RUNX1-like, DUX4 fusions, ZNF384 fusions, BCR-ABL1/Ph-like, high hyperdiploidy, and KMT2A fusions), we defined six additional gene expression subgroups: G9 was associated with both PAX5 and CRLF2 fusions; G10 and G11 with mutations in PAX5 (p.P80R) and IKZF1 (p.N159Y), respectively; G12 with IGH-CEBPE fusion and mutations in ZEB2 (p.H1038R); and G13 and G14 with TCF3/4-HLF and NUTM1 fusions, respectively. In pediatric BCP ALL, subgroups G2 to G5 and G7 (51 to 65/67 chromosomes) were associated with low-risk, G7 (with ≤50 chromosomes) and G9 were intermediate-risk, whereas G1, G6, and G8 were defined as high-risk subgroups. In adult BCP ALL, G1, G2, G6, and G8 were associated with high risk, while G4, G5, and G7 had relatively favorable outcomes. This large-scale transcriptome sequence analysis of BCP ALL revealed distinct molecular subgroups that reflect discrete pathways of BCP ALL, informing disease classification and prognostic stratification. The combined results strongly advocate that RNA sequencing be introduced into the clinical diagnostic workup of BCP ALL.
Collapse
Affiliation(s)
- Jian-Feng Li
- State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, National Research Center for Translational Medicine, Rui-Jin Hospital, Shanghai Jiao Tong University School of Medicine and School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, 200025 Shanghai, China
| | - Yu-Ting Dai
- State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, National Research Center for Translational Medicine, Rui-Jin Hospital, Shanghai Jiao Tong University School of Medicine and School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, 200025 Shanghai, China
| | - Henrik Lilljebjörn
- Department of Laboratory Medicine, Division of Clinical Genetics, Lund University, 22184 Lund, Sweden
| | - Shu-Hong Shen
- Key Laboratory of Pediatric Hematology and Oncology, Ministry of Health, Department of Hematology and Oncology, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, 200127 Shanghai, China
| | - Bo-Wen Cui
- State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, National Research Center for Translational Medicine, Rui-Jin Hospital, Shanghai Jiao Tong University School of Medicine and School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, 200025 Shanghai, China
| | - Ling Bai
- State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, National Research Center for Translational Medicine, Rui-Jin Hospital, Shanghai Jiao Tong University School of Medicine and School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, 200025 Shanghai, China
| | - Yuan-Fang Liu
- State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, National Research Center for Translational Medicine, Rui-Jin Hospital, Shanghai Jiao Tong University School of Medicine and School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, 200025 Shanghai, China
| | - Mao-Xiang Qian
- Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, TN 38105
| | - Yasuo Kubota
- Department of Pediatrics, Graduate School of Medicine, The University of Tokyo, 1138654 Tokyo, Japan
| | - Hitoshi Kiyoi
- Department of Hematology and Oncology, Nagoya University Graduate School of Medicine, 4668550 Nagoya, Japan
| | - Itaru Matsumura
- Division of Hematology and Rheumatology, Kinki University Faculty of Medicine, 5778502 Osaka, Japan
| | - Yasushi Miyazaki
- Department of Hematology, Atomic Bomb Disease Institute, Nagasaki University, 8528521 Nagasaki, Japan
| | - Linda Olsson
- Department of Laboratory Medicine, Division of Clinical Genetics, Lund University, 22184 Lund, Sweden
| | - Ah Moy Tan
- Department of Paediatrics, KK Women's & Children's Hospital, 229899 Singapore
| | - Hany Ariffin
- Paediatric Haematology-Oncology Unit, University of Malaya Medical Centre, 59100 Kuala Lumpur, Malaysia
| | - Jing Chen
- Key Laboratory of Pediatric Hematology and Oncology, Ministry of Health, Department of Hematology and Oncology, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, 200127 Shanghai, China
| | - Junko Takita
- Department of Pediatrics, Graduate School of Medicine, Kyoto University, 6068501 Kyoto, Japan
| | - Takahiko Yasuda
- Clinical Research Center, Nagoya Medical Center, National Hospital Organization, 4600001 Nagoya, Japan
| | - Hiroyuki Mano
- National Cancer Center Research Institute, 1040045 Tokyo, Japan
| | - Bertil Johansson
- Department of Laboratory Medicine, Division of Clinical Genetics, Lund University, 22184 Lund, Sweden
- Department of Clinical Genetics, University and Regional Laboratories, Region Skåne, Lund 22185, Sweden
| | - Jun J Yang
- Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, TN 38105
- Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN 38105
| | - Allen Eng-Juh Yeoh
- Centre for Translational Research in Acute Leukaemia, Department of Paediatrics, Yong Loo Lin School of Medicine, National University of Singapore, 119228 Singapore
| | - Fumihiko Hayakawa
- Department of Pathophysiological Laboratory Sciences, Nagoya University Graduate School of Medicine, 4618673 Nagoya, Japan
| | - Zhu Chen
- State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, National Research Center for Translational Medicine, Rui-Jin Hospital, Shanghai Jiao Tong University School of Medicine and School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, 200025 Shanghai, China;
- Key Laboratory of Systems Biomedicine, Ministry of Education, Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, Shanghai 200240, China
- Pôle de Recherches Sino-Français en Science du Vivant et Génomique, Laboratory of Molecular Pathology, Rui-Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Ching-Hon Pui
- Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN 38105;
| | - Thoas Fioretos
- Department of Laboratory Medicine, Division of Clinical Genetics, Lund University, 22184 Lund, Sweden;
- Department of Clinical Genetics, University and Regional Laboratories, Region Skåne, Lund 22185, Sweden
| | - Sai-Juan Chen
- State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, National Research Center for Translational Medicine, Rui-Jin Hospital, Shanghai Jiao Tong University School of Medicine and School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, 200025 Shanghai, China;
- Key Laboratory of Systems Biomedicine, Ministry of Education, Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, Shanghai 200240, China
- Pôle de Recherches Sino-Français en Science du Vivant et Génomique, Laboratory of Molecular Pathology, Rui-Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Jin-Yan Huang
- State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, National Research Center for Translational Medicine, Rui-Jin Hospital, Shanghai Jiao Tong University School of Medicine and School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, 200025 Shanghai, China;
- Pôle de Recherches Sino-Français en Science du Vivant et Génomique, Laboratory of Molecular Pathology, Rui-Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| |
Collapse
|
|
50
|
Su H, Hu J, Huang L, Yang Y, Thenoz M, Kuchmiy A, Hu Y, Li P, Feng H, Zhou Y, Taghon T, Van Vlierberghe P, Qing G, Chen Z, Liu H. SHQ1 regulation of RNA splicing is required for T-lymphoblastic leukemia cell survival. Nat Commun 2018; 9:4281. [PMID: 30323192 PMCID: PMC6189109 DOI: 10.1038/s41467-018-06523-4] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2018] [Accepted: 09/06/2018] [Indexed: 12/21/2022] Open
Abstract
T-acute lymphoblastic leukemia (T-ALL) is an aggressive hematologic malignancy with complicated heterogeneity. Although expression profiling reveals common elevated genes in distinct T-ALL subtypes, little is known about their functional role(s) and regulatory mechanism(s). We here show that SHQ1, an H/ACA snoRNP assembly factor involved in snRNA pseudouridylation, is highly expressed in T-ALL. Mechanistically, oncogenic NOTCH1 directly binds to the SHQ1 promoter and activates its transcription. SHQ1 depletion induces T-ALL cell death in vitro and prolongs animal survival in murine T-ALL models. RNA-Seq reveals that SHQ1 depletion impairs widespread RNA splicing, and MYC is one of the most prominently downregulated genes due to inefficient splicing. MYC overexpression significantly rescues T-ALL cell death resulted from SHQ1 inactivation. We herein report a mechanism of NOTCH1–SHQ1–MYC axis in T-cell leukemogenesis. These findings not only shed light on the role of SHQ1 in RNA splicing and tumorigenesis, but also provide additional insight into MYC regulation. T-acute lymphoblastic leukemia is an aggressive cancer. Here the authors provide insights into the functional role of SHQ1, an H/ACA snoRNP assembly factor involved in snRNA pseudouridylation, in T-lymphoblastic leukemia cell survival through regulating the maturation of MYC mRNA.
Collapse
Affiliation(s)
- Hexiu Su
- Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.,Medical Research Institute, Wuhan University, Wuhan, 430071, China
| | - Juncheng Hu
- Medical Research Institute, Wuhan University, Wuhan, 430071, China
| | - Liang Huang
- Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Yang Yang
- College of Life Sciences, Wuhan University, Wuhan, 430072, China
| | - Morgan Thenoz
- Department of Biomolecular Medicine, Ghent University, Ghent, 9000, Belgium
| | - Anna Kuchmiy
- Department of Clinical Chemistry, Microbiology and Immunology, Ghent University, Ghent, 9000, Belgium
| | - Yufeng Hu
- Zhongnan Hospital of Wuhan University, Wuhan, 430071, China
| | - Peng Li
- South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, 510530, China
| | - Hui Feng
- Department of Pharmacology and Department of Medicine, Cancer Research Center, Section of Hematology and Medical Oncology, Boston University School of Medicine, Boston, MA, 02118, USA
| | - Yu Zhou
- College of Life Sciences, Wuhan University, Wuhan, 430072, China
| | - Tom Taghon
- Department of Clinical Chemistry, Microbiology and Immunology, Ghent University, Ghent, 9000, Belgium
| | | | - Guoliang Qing
- Medical Research Institute, Wuhan University, Wuhan, 430071, China.,Zhongnan Hospital of Wuhan University, Wuhan, 430071, China
| | - Zhichao Chen
- Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
| | - Hudan Liu
- Medical Research Institute, Wuhan University, Wuhan, 430071, China. .,Zhongnan Hospital of Wuhan University, Wuhan, 430071, China.
| |
Collapse
|