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Volkov DV, Stepanova VM, Rubtsov YP, Stepanov AV, Gabibov AG. Protein Tyrosine Phosphatase CD45 As an Immunity Regulator and a Potential Effector of CAR-T therapy. Acta Naturae 2023; 15:17-26. [PMID: 37908772 PMCID: PMC10615191 DOI: 10.32607/actanaturae.25438] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2023] [Accepted: 09/12/2023] [Indexed: 11/02/2023] Open
Abstract
The leukocyte common antigen CD45 is a receptor tyrosine phosphatase and one of the most prevalent antigens found on the surface of blood cells. CD45 plays a crucial role in the initial stages of signal transmission from receptors of various immune cell types. Immunodeficiency, autoimmune disorders, and oncological diseases are frequently caused by gene expression disorders and imbalances in CD45 isoforms. Despite extensive research into the structure and functions of CD45, the molecular mechanisms behind its role in transmitting signals from T-cell receptors and chimeric antigen receptors remain not fully understood. It is of utmost importance to comprehend the structural features of CD45 and its function in regulating immune system cell activation to study oncological diseases and the impact of CD45 on lymphocytes and T cells modified by chimeric antigen receptors.
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Affiliation(s)
- D. V. Volkov
- M.M. Shemyakin and Yu.A. Ovchinnikov Institute of Bioorganic Chemistry of the Russian Academy of Sciences, Moscow, 117997 Russian Federation
| | - V. M. Stepanova
- M.M. Shemyakin and Yu.A. Ovchinnikov Institute of Bioorganic Chemistry of the Russian Academy of Sciences, Moscow, 117997 Russian Federation
| | - Y. P. Rubtsov
- M.M. Shemyakin and Yu.A. Ovchinnikov Institute of Bioorganic Chemistry of the Russian Academy of Sciences, Moscow, 117997 Russian Federation
| | - A. V. Stepanov
- M.M. Shemyakin and Yu.A. Ovchinnikov Institute of Bioorganic Chemistry of the Russian Academy of Sciences, Moscow, 117997 Russian Federation
| | - A. G. Gabibov
- M.M. Shemyakin and Yu.A. Ovchinnikov Institute of Bioorganic Chemistry of the Russian Academy of Sciences, Moscow, 117997 Russian Federation
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2
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Abdollahi P, Köhn M, Børset M. Protein tyrosine phosphatases in multiple myeloma. Cancer Lett 2020; 501:105-113. [PMID: 33290866 DOI: 10.1016/j.canlet.2020.11.042] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2020] [Revised: 11/24/2020] [Accepted: 11/26/2020] [Indexed: 12/28/2022]
Abstract
Many cell signaling pathways are activated or deactivated by protein tyrosine phosphorylation and dephosphorylation, catalyzed by protein tyrosine kinases (PTKs) and protein tyrosine phosphatases (PTPs), respectively. Even though PTPs are as important as PTKs in this process, their role has been neglected for a long time. Multiple myeloma (MM) is a cancer of plasma cells, which is characterized by production of monoclonal immunoglobulin, anemia and destruction of bone. MM is still incurable with high relapse frequency after treatment. In this review, we highlight the PTPs that were previously described in MM or have a role that can be relevant in a myeloma context. Our purpose is to show that despite the importance of PTPs in MM pathogenesis, many unanswered questions in this field need to be addressed. This might help to detect novel treatment strategies for MM patients.
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Affiliation(s)
- Pegah Abdollahi
- Department of Clinical and Molecular Medicine, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology (NTNU), Trondheim, Norway; Clinic of Medicine, St. Olavs Hospital, Trondheim, Norway; Faculty of Biology, Institute of Biology III, University of Freiburg, 79104, Freiburg, Germany; Signalling Research Centres BIOSS and CIBSS, University of Freiburg, 79104, Freiburg, Germany.
| | - Maja Köhn
- Faculty of Biology, Institute of Biology III, University of Freiburg, 79104, Freiburg, Germany; Signalling Research Centres BIOSS and CIBSS, University of Freiburg, 79104, Freiburg, Germany.
| | - Magne Børset
- Department of Clinical and Molecular Medicine, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology (NTNU), Trondheim, Norway; Department of Immunology and Transfusion Medicine, St. Olavs Hospital, Trondheim, Norway.
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3
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Zhang ZJ, Wang KP, Mo JG, Xiong L, Wen Y. Photodynamic therapy regulates fate of cancer stem cells through reactive oxygen species. World J Stem Cells 2020; 12:562-584. [PMID: 32843914 PMCID: PMC7415247 DOI: 10.4252/wjsc.v12.i7.562] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/26/2020] [Revised: 05/17/2020] [Accepted: 05/21/2020] [Indexed: 02/06/2023] Open
Abstract
Photodynamic therapy (PDT) is an effective and promising cancer treatment. PDT directly generates reactive oxygen species (ROS) through photochemical reactions. This oxygen-dependent exogenous ROS has anti-cancer stem cell (CSC) effect. In addition, PDT may also increase ROS production by altering metabolism, endoplasmic reticulum stress, or potential of mitochondrial membrane. It is known that the half-life of ROS in PDT is short, with high reactivity and limited diffusion distance. Therefore, the main targeting position of PDT is often the subcellular localization of photosensitizers, which is helpful for us to explain how PDT affects CSC characteristics, including differentiation, self-renewal, apoptosis, autophagy, and immunogenicity. Broadly speaking, excess ROS will damage the redox system and cause oxidative damage to molecules such as DNA, change mitochondrial permeability, activate unfolded protein response, autophagy, and CSC resting state. Therefore, understanding the molecular mechanism by which ROS affect CSCs is beneficial to improve the efficiency of PDT and prevent tumor recurrence and metastasis. In this article, we review the effects of two types of photochemical reactions on PDT, the metabolic processes, and the biological effects of ROS in different subcellular locations on CSCs.
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Affiliation(s)
- Zi-Jian Zhang
- Department of General Surgery, Second Xiangya Hospital, Central South University, Changsha 410011, Hunan Province, China
| | - Kun-Peng Wang
- Department of General Surgery, Taizhou Central Hospital (Taizhou University Hospital), Taizhou 318000, Zhejiang Province, China
| | - Jing-Gang Mo
- Department of General Surgery, Taizhou Central Hospital (Taizhou University Hospital), Taizhou 318000, Zhejiang Province, China
| | - Li Xiong
- Department of General Surgery, Second Xiangya Hospital, Central South University, Changsha 410011, Hunan Province, China
| | - Yu Wen
- Department of General Surgery, Second Xiangya Hospital, Central South University, Changsha 410011, Hunan Province, China.
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Shahzad MN, Ijaz I, Naqvi SSZH, Yan C, Lin F, Li S, Huang C. Association between interleukin gene polymorphisms and multiple myeloma susceptibility. Mol Clin Oncol 2020; 12:212-224. [PMID: 32064097 PMCID: PMC7016519 DOI: 10.3892/mco.2020.1979] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2018] [Accepted: 06/10/2019] [Indexed: 12/16/2022] Open
Abstract
The present study performed a retrospective observational study in order to investigate the relationship between the interleukin family gene polymorphisms and risk of multiple myeloma (MM), based on sixteen case-control studies that contained 2,597 patients with MM and 3,851 controls. The results demonstrated that the genotypes IL-6 and IL-1 GG increased the risk of MM by approximately 40.8 and 80.2% compared with the genotypes AA and CC [odds ratio (OR)=1.14, 95% confidence interval (CI), 0.88-1.47, and OR=1.16, 95% CI, 0.61-2.19; respectively]. The results also revealed a significant association between T:C polymorphism of the IL-6 and IL-10 and the risk of MM (TC/CC: OR=1.37, 95% CI, 0.88-2.16 and TT/CC: OR=1.26, 95% CI, 0.77-2.06, respectively). Additionally, no significant association was identified between the C:A polymorphisms of the IL-6 (rs8192284) and IL-10 (rs1800872) receptors and the overall risk of MM (P>0.05). G:C polymorphisms of the IL-1β1464G>C and IL-6572G>C significantly increased the risk of MM (P<0.05). However, it has been determined that there is a significant association between the C:T polymorphism of the IL-1α-889C>T and IL-1β-3737C>T and the risk of MM (P<0.001). Subgroup analysis revealed that the detection of G:A polymorphisms in the IL-6 promoter (OR=1.05, 95% CI, 0.78-1.44) is more accurate in MM samples of the Asian population (OR=1.24, 95% CI, 0.92-1.74). In addition, no significant association was identified between the IL gene polymorphisms in MM samples categorized by ethnicity and the IL family type (P=0.27). These single nucleotide polymorphism loci may be the appropriate gene markers for gene screening and a promising therapeutic strategy in the prognostics of patients with MM.
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Affiliation(s)
- Muhamaad Naveed Shahzad
- Stem Cell Laboratory, Department of Hematology, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan 646000, P.R. China
| | - Iqra Ijaz
- Sino-German Department for The Treatment of Ovarian Tumors, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan 646000, P.R. China
| | - Syed Shah Zaman Haider Naqvi
- Department of Diabetes and Endocrinology, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan 646000, P.R. China
| | - Cheng Yan
- Stem Cell Laboratory, Department of Hematology, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan 646000, P.R. China
| | - Fanli Lin
- Stem Cell Laboratory, Department of Hematology, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan 646000, P.R. China
| | - Shutan Li
- Stem Cell Laboratory, Department of Hematology, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan 646000, P.R. China
| | - Chunlan Huang
- Stem Cell Laboratory, Department of Hematology, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan 646000, P.R. China
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Shvartsur A, Givechian KB, Garban H, Bonavida B. Overexpression of RKIP and its cross-talk with several regulatory gene products in multiple myeloma. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2017; 36:62. [PMID: 28476134 PMCID: PMC5420138 DOI: 10.1186/s13046-017-0535-z] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/22/2016] [Accepted: 04/26/2017] [Indexed: 12/27/2022]
Abstract
Multiple myeloma (MM) is a clonal plasma-cell neoplastic disorder arising from an indolent premalignant disease known as monoclonal gammopathy of undetermined significance (MGUS). MM is a biologically complex heterogeneous disease reflected by its variable clinical responses of patients receiving the same treatment. Therefore, a molecular identification of stage-specific biomarkers will support a more individualized precise diagnostic/prognostic approach, an effective therapeutic regime, and will assist in the identification of novel therapeutic molecular targets. The metastatic suppressor/anti-resistance factor Raf-1 kinase inhibitor protein (RKIP) is poorly expressed in the majority of cancers and is often almost absent in metastatic tumors. RKIP inhibits the Raf/MEK/ERK1/2 and the NF-κB pathways. Whereby all tumors examined exhibited low levels of RKIP, in contrast, our recent findings demonstrated that RKIP is overexpressed primarily in its inactive phosphorylated form in MM cell lines and patient-derived tumor tissues. The underlying mechanism of RKIP overexpression in MM, in contrast to other tumors, is not known. We examined transcriptomic datasets on Oncomine platform (Life Technologies) for the co-expression of RKIP and other gene products in both pre-MM and MM. The transcription of several gene products was found to be either commonly overexpressed (i.e., RKIP, Bcl-2, and DR5) or underexpressed (i.e., Bcl-6 and TNFR2) in both pre-MM and MM. Noteworthy, a significant inverse correlation of differentially expressed pro-apoptotic genes was observed in pre-MM: overexpression of Fas and TNF-α and underexpression of YY1 versus expression of anti-apoptotic genes in MM: overexpression of YY1 and underexpression of Fas and TNF-α. Based on the analysis on mRNA levels and reported studies on protein levels of the above various genes, we have constructed various schemes that illustrate the possible cross-talks between RKIP (active/inactive) and the identified gene products that underlie the mechanism of RKIP overexpression in MM. Clearly, such cross-talks would need to be experimentally validated in both MM cell lines and patient-derived tumor tissues. If validated, the differential molecular signatures between pre-MM and MM might lead to a more precise diagnosis/prognosis of the disease and disease stages and will also identify novel molecular therapeutic targets for pre-MM and MM.
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Affiliation(s)
- Anna Shvartsur
- Department of Microbiology, Immunology, and Molecular Genetics, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, 90095, USA
| | - Kevin B Givechian
- Department of Biological Sciences, USC Dana and David Dornsife College of Letters, Arts and Sciences at the University of Southern California, Los Angeles, CA, 90089, USA
| | - Hermes Garban
- California NanoSystems Institute (CnSI), University of California Los Angeles, Los Angeles, CA, 90095, USA
| | - Benjamin Bonavida
- Department of Microbiology, Immunology, and Molecular Genetics, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, 90095, USA.
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6
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Abdollahi P, Vandsemb EN, Hjort MA, Misund K, Holien T, Sponaas AM, Rø TB, Slørdahl TS, Børset M. Src Family Kinases Are Regulated in Multiple Myeloma Cells by Phosphatase of Regenerating Liver-3. Mol Cancer Res 2016; 15:69-77. [DOI: 10.1158/1541-7786.mcr-16-0212] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2016] [Revised: 09/19/2016] [Accepted: 09/22/2016] [Indexed: 11/16/2022]
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Rosean TR, Tompkins VS, Tricot G, Holman CJ, Olivier AK, Zhan F, Janz S. Preclinical validation of interleukin 6 as a therapeutic target in multiple myeloma. Immunol Res 2014; 59:188-202. [PMID: 24845460 PMCID: PMC4209159 DOI: 10.1007/s12026-014-8528-x] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Studies on the biologic and molecular genetic underpinnings of multiple myeloma (MM) have identified the pleiotropic, pro-inflammatory cytokine, interleukin-6 (IL-6), as a factor crucial to the growth, proliferation and survival of myeloma cells. IL-6 is also a potent stimulator of osteoclastogenesis and a sculptor of the tumor microenvironment in the bone marrow of patients with myeloma. This knowledge has engendered considerable interest in targeting IL-6 for therapeutic purposes, using a variety of antibody- and small-molecule-based therapies. However, despite the early recognition of the importance of IL-6 for myeloma and the steady progress in our knowledge of IL-6 in normal and malignant development of plasma cells, additional efforts will be required to translate the promise of IL-6 as a target for new myeloma therapies into significant clinical benefits for patients with myeloma. This review summarizes published research on the role of IL-6 in myeloma development and describes ongoing efforts by the University of Iowa Myeloma Multidisciplinary Oncology Group to develop new approaches to the design and testing of IL-6-targeted therapies and preventions of MM.
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Affiliation(s)
- Timothy R Rosean
- Interdisciplinary Graduate Program in Immunology, Carver College of Medicine, University of Iowa, Iowa City, IA, USA
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8
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Verdelli D, Nobili L, Todoerti K, Mosca L, Fabris S, D'Anca M, Pellegrino E, Piva R, Inghirami G, Capelli C, Introna M, Baldini L, Chiaramonte R, Lombardi L, Neri A. Molecular events underlying interleukin-6 independence in a subclone of the CMA-03 multiple myeloma cell line. Genes Chromosomes Cancer 2013; 53:154-67. [PMID: 24327544 DOI: 10.1002/gcc.22127] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2013] [Revised: 10/10/2013] [Accepted: 10/14/2013] [Indexed: 11/08/2022] Open
Abstract
We explored the molecular mechanisms involved in the establishement of CMA-03/06, an IL-6-independent variant of the multiple myeloma cell line CMA-03 previously generated in our Institution. CMA-03/06 cells grow in the absence of IL-6 with a doubling time comparable with that of CMA-03 cells; neither the addition of IL6 (IL-6) to the culture medium nor co-culture with multipotent mesenchymal stromal cells increases the proliferation rate, although they maintain the responsiveness to IL-6 stimulation as demonstrated by STAT1, STAT3, and STAT5 induction. IL-6 independence of CMA-03/06 cells is not apparently due to the development of an autocrine IL-6 loop, nor to the observed moderate constitutive activation of STAT5 and STAT3, since STAT3 silencing does not affect cell viability or proliferation. When compared to the parental cell line, CMA-03/06 cells showed an activated pattern of the NF-κB pathway. This finding is supported by gene expression profiling (GEP) analysis identifying an appreciable fraction of modulated genes (28/308) in the CMA-03/06 subclone reported to be involved in this pathway. Furthermore, although more resistant to apoptotic stimuli compared to the parental cell line, CMA-03/06 cells display a higher sensibility to NF-κB inhibition induced by bortezomib. Finally, GEP analysis suggests an involvement of a number of cytokines, which might contribute to IL-6 independence of CMA-03/06 by stimulating growth and antiapoptotic processes. In conclusion, the parental cell-line CMA-03 and its variant CMA-03/06 represent a suitable model to further investigate molecular mechanisms involved in the IL-6-independent growth of myeloma cells.
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Affiliation(s)
- Donata Verdelli
- Department of Clinical Sciences and Community Health, University of Milano and Hematology-CTMO, Fondazione Cà Granda, IRCCS Policlinico, Milano, Italy
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9
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Baritaki S, Huerta-Yepez S, Cabrava-Haimandez MDL, Sensi M, Canevari S, Libra M, Penichet M, Chen H, Berenson JR, Bonavida B. Unique Pattern of Overexpression of Raf-1 Kinase Inhibitory Protein in Its Inactivated Phosphorylated Form in Human Multiple Myeloma. ACTA ACUST UNITED AC 2011; 2. [PMID: 24286018 DOI: 10.1615/forumimmundisther.v2.i2.90] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Abstract
Multiple myeloma (MM) is the second most common hematological and incurable malignancy of plasma cells with low proliferative activity in the bone marrow. MM patients initially respond to conventional therapy, however, many develop resistance and recurrences occur. We have identified RKIP as a novel gene product that is differentially overexpressed in MM cell lines and MM tissues compared to other studied tumors and normal bone marrow. This overexpression consisted, in large part, of a phosphorylated inactive form of RKIP at Ser153 (p-Ser153 RKIP). In contrast to RKIP, p-Ser153 RKIP lacks its ability to inhibit the MAPK signaling pathway. The overexpression of p-Ser153 RKIP in MM cell lines and MM tissues was further validated in a mouse model carrying a human MM xenograft, namely, LAGλ-1B. Bioinformatic analyses from databases support the presence of increased RKIP mRNA expression in MM compared to normal plasma cells. In these databases, high RKIP levels in MM are also correlated with the nonhyperdiploid status and the presence of IgH translocations, parameters that generally display more aggressive clinical features and shorter patients' survival irrespective of the treatment. Since RKIP expression regulates both the NF-κB and MAPK survival pathways, the overexpression of "inactive" p-Ser153 RKIP in MM might contribute positively to the overall cell survival/antiapoptotic phenotype and drug resistance of MM through the constitutive activation of survival pathways and downstream the transcription of anti-apoptotic gene products. The overexpression of RKIP and p-Ser153 RKIP in MM is the first demonstration in the literature, since in most tumor tissues the expression of RKIP is very low and the expression of p-Ser153 RKIP is much lower. The relationship between the levels of active RKIP and inactive p-Ser153 RKIP in MM may be of prognostic significance, and the regulation of RKIP activity may be a target for therapeutic intervention.
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Affiliation(s)
- Stavroula Baritaki
- Department of Microbiology, Immunology and Molecular Genetics, Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, University of California, Los Angeles, CA
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Ruela-de-Sousa RR, Queiroz KCS, Peppelenbosch MP, Fuhler GM. Reversible phosphorylation in haematological malignancies: potential role for protein tyrosine phosphatases in treatment? Biochim Biophys Acta Rev Cancer 2010; 1806:287-303. [PMID: 20659529 DOI: 10.1016/j.bbcan.2010.07.007] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2010] [Revised: 07/16/2010] [Accepted: 07/20/2010] [Indexed: 01/12/2023]
Abstract
Most aspects of leukocyte physiology are under the control of reversible tyrosine phosphorylation. It is clear that excessive phosphorylation of signal transduction elements is a pivotal element of many different pathologies including haematological malignancies and accordingly, strategies that target such phosphorylation have clinically been proven highly successful for treatment of multiple types of leukemias and lymphomas. Cellular phosphorylation status is dependent on the resultant activity of kinases and phosphatases. The cell biology of the former is now well understood; for most cellular phosphoproteins we now know the kinases responsible for their phosphorylation and we understand the principles of their aberrant activity in disease. With respect to phosphatases, however, our knowledge is much patchier. Although the sequences of whole genomes allow us to identify phosphatases using in silico methodology, whereas transcription profiling allows us to understand how phosphatase expression is regulated during disease, most functional questions as to substrate specificity, dynamic regulation of phosphatase activity and potential for therapeutic intervention are still to a large degree open. Nevertheless, recent studies have allowed us to make meaningful statements on the role of tyrosine phosphatase activity in the three major signaling pathways that are commonly affected in leukemias, i.e. the Ras-Raf-ERK1/2, the Jak-STAT and the PI3K-PKB-mTOR pathways. Lessons learned from these pathways may well be applicable elsewhere in leukocyte biology as well.
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Affiliation(s)
- Roberta R Ruela-de-Sousa
- Center for Experimental and Molecular Medicine, Academic Medical Center, Meibergdreef 9 1105 AZ Amsterdam, The Netherlands
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11
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Abstract
Interleukin-6 (IL-6) plays a critical role in the natural history of human plasma cell neoplasms (PCNs), such as plasma cell myeloma and plasmacytoma (PCT). IL-6 is also at the center of neoplastic plasma cell transformation in BALB/c (C) mice carrying a transgene, H2-L(d)-IL6, that encodes human IL-6 under control of the major histocompatibility complex H2-L(d) promoter: strain C.H2-L(d)-IL6. These mice are prone to PCT, but tumor development is incomplete with long latencies ( approximately 40% PCT at 12 months of age). To generate a more robust mouse model of IL-6-dependent PCN, we intercrossed strain C.H2-L(d)-IL6 with strains C.iMyc(Emu) or C.iMyc(Calpha), 2 interrelated gene-insertion models of the chromosomal T(12;15) translocation causing deregulated expression of Myc in mouse PCT. Deregulation of MYC is also a prominent feature of human PCN. We found that double-transgenic C.H2-L(d)-IL6/iMyc(Emu) and C.H2-L(d)-IL6/iMyc(Calpha) mice develop PCT with full penetrance (100% tumor incidence) and short latencies (3-6 months). The mouse tumors mimic molecular hallmarks of their human tumor counterparts, including elevated IL-6/Stat3/Bcl-X(L) signaling. The newly developed mouse strains may provide a good preclinical research tool for the design and testing of new approaches to target IL-6 in treatment and prevention of human PCNs.
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12
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Gertz MA. New targets and treatments in multiple myeloma: Src family kinases as central regulators of disease progression. Leuk Lymphoma 2009; 49:2240-5. [PMID: 19052970 DOI: 10.1080/10428190802475311] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Multiple myeloma is a malignant condition that most commonly occurs in the seventh decade of life. Recent improvements in treatment may result in a more favourable outlook for recently diagnosed patients. Multiple myeloma is an incurable clonal B-cell malignancy, which is initially responsive to conventional chemotherapy; one-third of the patients achieve complete remission but multidrug resistance eventually develops. Although autologous stem cell transplantation remains an important option, many older patients are less tolerant to the toxicity associated with conditioning treatment, as well as being intrinsically less likely to do well after transplantation. Most patients eventually relapse with or without transplantation, and salvage therapy is only moderately effective. Thalidomide and subsequently, lenalidomide and bortezomib, have demonstrated improved outcomes for these patients, as well as proving efficacious in front-line regimens. A deeper understanding of the molecular mechanisms underlying multiple myeloma has given rise to novel targeted approaches. This review will focus in particular on Src-dependent signalling pathways, reflecting the expanding realisation of the critical and ubiquitous role of Src family kinases (SFKs) in normal and abnormal hematopoiesis.
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Affiliation(s)
- Morie A Gertz
- Department of Internal Medicine, Mayo Clinic, Rochester, MN 55905, USA.
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Nakazato T, Suzuki K, Mihara A, Sanada Y, Kakimoto T. Refractory plasmablastic type myeloma with multiple extramedullary plasmacytomas and massive myelomatous effusion: remarkable response with a combination of thalidomide and dexamethasone. Intern Med 2009; 48:1827-32. [PMID: 19834276 DOI: 10.2169/internalmedicine.48.2142] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
A 74-year-old man with multiple myeloma was refractory to melphalan/prednisolone (MP), high-dose dexamethasone and VAD chemotherapy. He had the following poor prognostic factors: 1) multiple extramedullary plasmacytomas, 2) massive myelomatous effusion, 3) increasing immature myeloma cells with plasmablastic morphology, and 4) predominance of MPC1-CD49e-CD45+ phenotype immature myeloma cells. Combination therapy with thalidomide and dexamethasone resulted in a rapid response and a partial remission despite his multiple poor prognostic factors. The present case suggests that combination therapy with thalidomide and dexamethasone is still an alternative treatment regimen for resistant extramedullary plasmacytoma with a plasmablastic morphology.
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Affiliation(s)
- Tomonori Nakazato
- Department of Hematology, Yokohama Municipal Citizens Hospital, Yokohama.
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14
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Ménoret E, Maïga S, Descamps G, Pellat-Deceunynck C, Fraslon C, Cappellano M, Moreau P, Bataille R, Amiot M. IL-21 stimulates human myeloma cell growth through an autocrine IGF-1 loop. THE JOURNAL OF IMMUNOLOGY 2008; 181:6837-42. [PMID: 18981102 DOI: 10.4049/jimmunol.181.10.6837] [Citation(s) in RCA: 33] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
IL-21 is a member of the type I cytokine family related most closely to IL-2 and IL-15. IL-21 is a pleiotropic cytokine, produced by T, NKT, and dendritic cells, which modulates lymphoid and myeloid cell functions. Besides its activities on normal lymphoid cells, it has been shown that IL-21 is a growth factor for myeloma cells. In the present study, we demonstrate that IL-21 generated myeloma colonies from 9 of 24 human myeloma cell lines (HMCL) in a collagen-based assay. Of major interest, the capacity of IL-21 to stimulate clonogenicity was restricted to CD45(-) HMCL. We found that IL-21 induced tyrosine phosphorylation of STAT-3, STAT-1, and Erk1/2. Interestingly, an Akt activation was observed lately after 30 min to 1 h of IL-21 stimulation, indicating that this Akt phosphorylation could be due to an IGF-1 autocrine loop. This hypothesis was sustained both by the fact that IL-21 treatment induced an IGF-1 mRNA synthesis and that an antagonistic anti-IGF-1 receptor mAb (AVE1642) strongly inhibits the IL-21-induced clonogenicity. Thus, we demonstrated by quantitative PCR that IL-21 induced clonogenicity through an autocrine IGF-1 secretion in HMCL and primary myeloma cells. Because we have previously demonstrated that CD45 phosphatase inhibits the IGF-1 signaling, this inhibitory effect of CD45 explains why the IL-21-induced clonogenicity was restricted to CD45(-) HMCL. These results support that therapy against IGF-1R, which are presently under investigation in multiple myeloma, could be beneficial, not only to suppress IGF-1-mediated myeloma cell growth, but also IL-21-mediated myeloma cell growth.
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Affiliation(s)
- Emmanuelle Ménoret
- Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche 892, Université de Nantes, Nantes Atlantique Universités, Nantes, France
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Saito N, Konishi K, Ohta S, Kondo T, Kato M, Hashino S, Takeda H, Asaka M, Ooi HK. Plural light chains in a single plasma cell of a monoclonal gammopathy undetermined significance case: An ultrastructural study. Hum Cell 2007; 20:10-4. [PMID: 17506772 DOI: 10.1111/j.1749-0774.2007.00026.x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
A 44-year-old man was found to have M-proteins of IgG consisting of kappa- and lambda-chains in serum without lymphadenopathy or splenomegaly. The serum concentrations of IgG, IgA and IgM were within normal limits. Bone marrow examination showed normal cellular marrow containing 6.3% of plasma cells with no abnormal features. No chromosomal abnormality was observed at all. The patient was diagnosed as having monoclonal gammopathy of undetermined significance. The bone marrow plasma cells possessed free kappa- and lambda-chains in Golgi apparatus, rough endoplasmic reticula and cytoplasmic matrices. Plural light chains were simultaneously produced with the same heavy chain in a plasma cell by immunoelectron microscopy. This is the first report in the world of a monoclonal gammopathy of undetermined significance producing plural light chains with the same heavy chain.
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Affiliation(s)
- Nagahito Saito
- Gastroenterology and Hematology Section, Hokkaido University Graduate School of Internal Medicine, Sapporo, Japan.
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Otsuyama KI, Asaoku H, Kawano MM. An increase in MPC-1- and MPC-1-CD45+ immature myeloma cells in the progressive states of bone marrow plasmacytosis: the revised phenotypic classification of monoclonal marrow plasmacytosis (MOMP-2005). Int J Hematol 2006; 83:39-43. [PMID: 16443550 DOI: 10.1532/ijh97.05112] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
The heterogeneity of bone marrow plasmacytosis is clearly analyzed by multicolor staining with anti-CD38 antibody. To date, at least 5 subpopulations of plasma cells have been identified in the bone marrow of multiple myeloma (MM) patients with regard to the expression of MPC-1, CD49e (VLA-5), and CD45: MPC-1(-)CD49e(-)CD45(+) proliferative immature cells, MPC-1(-)CD49e(-)CD45(-) immature myeloma cells, MPC-1(+)CD49e(-)CD45(-) and MPC-1(+)CD49e(-)CD45(+) intermediate myeloma cells, and MPC-1(+)CD49e(+)CD45(+) mature myeloma cells. We performed phenotypic analyses in 75 cases of monoclonal bone marrow plasmacytosis, including 46 cases of MM and 29 cases of monoclonal gammopathy of undetermined significance (MGUS). In 31 cases of progressive MM disease, MPC-1(-) immature and MPC-1(-)CD45(+) proliferative immature myeloma cells were significantly increased up to >25% and >10%, respectively, of the plasma cell fractions (CD38(++) cells), whereas there were no increases in MPC-1(-) or MPC-1(-)CD45(+) proliferative immature myeloma cells in 15 cases of stable disease. Interestingly, the proportions of MPC-1(-) and MPC-1(-)CD45(+) immature monoclonal plasma cells also increased in the 7 progressive cases of MGUS. Finally, we present the revised (2005) phenotypic classification of monoclonal marrow plasmacytosis (MOMP-2005).
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Affiliation(s)
- Ken-ichiro Otsuyama
- Department of Bio-Signal Analysis, AMES, Graduate School of Medicine, Yamaguchi University, Yamaguchi, Japan
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Yaccoby S. The phenotypic plasticity of myeloma plasma cells as expressed by dedifferentiation into an immature, resilient, and apoptosis-resistant phenotype. Clin Cancer Res 2006; 11:7599-606. [PMID: 16278377 PMCID: PMC1592552 DOI: 10.1158/1078-0432.ccr-05-0523] [Citation(s) in RCA: 66] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
PURPOSE We previously showed the ability of osteoclasts to support myeloma plasma cell survival and proliferation in vivo and ex vivo. The aim of the current study was to investigate osteoclast-induced phenotypic changes associated with long-term survival of myeloma cells in coculture. EXPERIMENTAL DESIGN CD138-selected myeloma plasma cells from 16 patients were cocultured with human osteoclasts for up to 20 weeks. RESULTS Precultured cells were typically CD45(low/intermediate) CD38(high) CD138(high), CD19(-)CD34(-). After >6 weeks, the phenotype of cocultured myeloma cells consistently shifted to cells expressing CD45(intermediate/high) CD19(low) CD34(low). Expression of CD38 and CD138 were reduced to subpopulations with CD38(intermediate) and CD138(low) levels. Morphologically, cocultured plasma cells became plasmablastic. Blocking interleukin-6 activity did not affect the immature phenotype of myeloma cells. The effect of dexamethasone on myeloma cells cultured alone or in cocultures at baseline and after 6 weeks of coculture was determined. When baseline myeloma cells were cultured alone, dexamethasone significantly increased the percentage of apoptotic cells over the spontaneous rate. Conversely, myeloma cells recovered from cocultures had high survival rates and were resistant to dexamethasone-induced apoptosis. Long-term coculture of normal CD34-expressing hematopoietic stem cells (HSC) resulted in loss of CD34 expression, suggesting a common mechanism for osteoclast-induced myeloma and HSC plasticity. CONCLUSIONS This study indicates that myeloma cells have plasticity expressed by their ability to reprogram, dedifferentiate, and acquire autonomous survival properties.
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Affiliation(s)
- Shmuel Yaccoby
- Myeloma Institute for Research and Therapy, University of Arkansas for Medical Sciences, Little Rock, 72205, USA.
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Kuroda Y, Sakai A, Okikawa Y, Munemasa S, Katayama Y, Hyodo H, Imagawa J, Takimoto Y, Okita H, Ohtaki M, Kimura A. The maturation of myeloma cells correlates with sensitivity to chemotherapeutic agents. Int J Hematol 2005; 81:335-41. [PMID: 15914366 DOI: 10.1532/ijh97.04189] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
We analyzed both morphologic and phenotypic findings of myeloma cells before and after chemotherapy in 21 patients with multiple myeloma. The morphologic analysis was based on the Greipp classification, and phenotypic analysis was performed by 3-color flow cytometry using the CD38 plasma gating method (Marrow plasma 38). Results with flow cytometry using a combination of MPC1, CD49e, and CD45 supported the morphologic findings for the myeloma cells. Treatment with 3 or 4 cycles of VAD (vincristine, doxorubicin, and dexamethasone) therapy was effective in reducing the total numbers of myeloma cells, but the proportion of immature myeloma cells increased after this treatment. However, the immature myeloma cells were reduced by high-dose melphalan (HD-Mel) therapy followed by autologous stem cell transplantation (ASCT). High-dose cyclophosphamide treatment for stem cell harvesting did not show an effect on the residual immature myeloma cells after VAD treatment. In addition, thalidomide was not effective in reducing the numbers of immature myeloma cells. These results suggest that VAD (3 or 4 cycles) therapy plus HD-Mel followed by ASCT is a reasonable treatment for multiple myeloma and that Marrow plasma 38 analysis is a useful method for monitoring the response of multiple myeloma to chemotherapy.
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Affiliation(s)
- Yoshiaki Kuroda
- Department of Hematology and Oncology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima734-8553, Japan
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McNeil N, Kim JS, Ried T, Janz S. Extraosseous IL-6 transgenic mouse plasmacytoma sometimes lacks Myc-activating chromosomal translocation. Genes Chromosomes Cancer 2005; 43:137-46. [PMID: 15751044 DOI: 10.1002/gcc.20172] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
The cellular oncogene MYC and plasma cell growth, differentiation, and survival factor IL-6 play critical roles in the natural history of human plasma cell neoplasms such as multiple myeloma (MM). Myc and IL-6 also are at the center of neoplastic plasma cell transformation in BALB/c mice that carry a human IL-6 transgene and, therefore, predictably develop plasmacytomas (PCTs). We showed previously that, much like advanced MM or human myeloma cell lines (HMCLs), in which MYC is frequently deregulated in cis because of complex cytogenetic aberrations juxtaposing MYC to immunoglobulin enhancers, IL-6 transgenic PCTs commonly deregulate Myc in cis by chromosomal translocation, predominantly T(12;15)(Igh-Myc). In this article, we show that, analogous to primary MM in which MYC is mostly deregulated in trans by signaling pathways converging at the MYC promoter, IL-6 transgenic PCTs sometimes develop in the absence of Myc translocations, thus activating Myc in trans. We present cytogenetic and molecular evidence on two IL-6 transgenic PCTs that contained overexpressed Myc protein but lacked T(12;15)(Igh-Myc) and two related Myc--deregulating translocations that juxtapose Myc to immunoglobulin light-chain instead of heavy-chain enhancers: T(6;15)(Igkappa-Pvt1) and T(15;16)(Pvt1-Iglambda). We conclude that Myc translocations are not strictly required for IL-6-driven PCT development in mice. IL-6 transgenic PCTs may provide a valuable model system for elucidating both trans and cis mechanisms of Myc deregulation of great relevance for MYC deregulation in human MM.
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Affiliation(s)
- Nicole McNeil
- Genetics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892-4256, USA
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Xu B, Makris A, Thornton C, Hennessy A. Glucocorticoids inhibit placental cytokines from cultured normal and preeclamptic placental explants. Placenta 2004; 26:654-60. [PMID: 16085044 DOI: 10.1016/j.placenta.2004.09.011] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/05/2004] [Revised: 09/22/2004] [Accepted: 09/22/2004] [Indexed: 11/19/2022]
Abstract
Glucocorticoids are used in pregnancy to enhance fetal lung maturity as well as to ameliorate antepartum and postpartum HELLP (hemolysis, elevated liver enzymes, and low platelet count) syndrome, but it is not clear if glucocorticoids can modulate placental cytokine production. The aim of this study is to examine the effect of glucocorticoids at equivalent doses used for fetal lung maturity on placental tissue production of cytokines (IL-10, IL-6 and TNF-alpha). Placental biopsies were taken from the decidual surface of term placentas of normal pregnancy (n = 5) and preeclampsia (n = 5). Villous explants were cultured with increasing concentrations of glucocorticoids (betamethasone and methyl-prednisolone, 0.0025 microM, 0.25 microM and 25 microM). The dose effect of glucocorticoids on cytokines (TNF-alpha, IL-6 and IL-10) production was examined using ELISA. There was a stepwise reduction of TNF-alpha (23.6-97.5% reduction) and IL-6 (13.7-71% reduction) with increasing doses of betamethasone and methyl-prednisolone from placentas of women with preeclampsia and normal pregnancy. However, IL-10 was not altered in conditioned medium by increasing doses of glucocorticoids. Our data suggest that the ratio of pro-inflammatory to anti-inflammatory cytokine (Th1/Th2) is potentially altered by exogenous glucocorticoids. These changes have a favourable effect on the ratio in preeclampsia with a reduction in the potentially vascular active pro-inflammatory cytokines but without altering or decreasing the necessary anti-inflammatory cytokine IL-10 production in placental tissue.
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Affiliation(s)
- B Xu
- Vascular Immunology Research Laboratory, The Heart Research Institute, University of Sydney, Camperdown, NSW, Australia.
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