scholarly journals Mechanisms of Drug Resistance in Relapse and Refractory Multiple Myeloma

2015 ◽  
Vol 2015 ◽  
pp. 1-17 ◽  
Author(s):  
Wen-Chi Yang ◽  
Sheng-Fung Lin
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Drug Resistance ◽  
Hematological Malignancy ◽  
Clonal Evolution ◽  
Resistance Mechanisms ◽  
Bone Marrow Microenvironment ◽  
Molecular Targeting ◽  
Resistance To Therapy ◽  
Programmed Death

Multiple myeloma (MM) is a hematological malignancy that remains incurable because most patients eventually relapse or become refractory to current treatments. Although the treatments have improved, the major problem in MM is resistance to therapy. Clonal evolution of MM cells and bone marrow microenvironment changes contribute to drug resistance. Some mechanisms affect both MM cells and microenvironment, including the up- and downregulation of microRNAs and programmed death factor 1 (PD-1)/PD-L1 interaction. Here, we review the pathogenesis of MM cells and bone marrow microenvironment and highlight possible drug resistance mechanisms. We also review a potential molecular targeting treatment and immunotherapy for patients with refractory or relapse MM.

scholarly journals Pathogenesis beyond the cancer clone(s) in multiple myeloma

Blood ◽  
2015 ◽  
Vol 125 (20) ◽  
pp. 3049-3058 ◽  
Author(s):  
Giada Bianchi ◽  
Nikhil C. Munshi
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Clonal Evolution ◽  
Bone Marrow Microenvironment ◽  
Plasma Cell Dyscrasia ◽  
Cancer Microenvironment ◽  
Resistance To Therapy ◽  
Cancer Pathogenesis ◽  
The Impact

Abstract Over the past 4 decades, basic research has provided crucial information regarding the cellular and molecular biology of cancer. In particular, the relevance of cancer microenvironment (including both cellular and noncellular elements) and the concept of clonal evolution and heterogeneity have emerged as important in cancer pathogenesis, immunologic escape, and resistance to therapy. Multiple myeloma (MM), a cancer of terminally differentiated plasma cells, is emblematic of the impact of cancer microenvironment and the role of clonal evolution. Although genetic and epigenetic aberrations occur in MM and evolve over time under the pressure of exogenous stimuli, they are also largely present in premalignant plasma cell dyscrasia such as monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM), suggesting that genetic mutations alone are necessary, but not sufficient, for myeloma transformation. The role of bone marrow microenvironment in mediating survival, proliferation, and resistance to therapy in myeloma is well established; and although an appealing speculation, its role in fostering the evolution of MGUS or SMM into MM is yet to be proven. In this review, we discuss MM pathogenesis with a particular emphasis on the role of bone marrow microenvironment.

scholarly journals NRF2 Is One of the Players Involved in Bone Marrow Mediated Drug Resistance in Multiple Myeloma

2018 ◽  
Vol 19 (11) ◽  
pp. 3503 ◽  
Author(s):  
Chia-Hung Yen ◽  
Hui-Hua Hsiao
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Drug Resistance ◽  
Hematologic Malignancy ◽  
Suppressor Cells ◽  
Resistance Mechanisms ◽  
Bone Marrow Microenvironment ◽  
Myeloma Cells ◽  
Functional Roles ◽  
Oxidative Stresses

Multiple myeloma with clonal plasma expansion in bone marrow is the second most common hematologic malignancy in the world. Though the improvement of outcomes from the achievement of novel agents in recent decades, the disease progresses and leads to death eventually due to the elusive nature of myeloma cells and resistance mechanisms to therapeutic agents. In addition to the molecular and genetic basis of resistance pathomechanisms, the bone marrow microenvironment also contributes to disease progression and confers drug resistance in myeloma cells. In this review, we focus on the current state of the literature in terms of critical bone marrow microenvironment components, including soluble factors, cell adhesion mechanisms, and other cellular components. Transcriptional factor nuclear factor erythroid-derived-2-like 2 (NRF2), a central regulator for anti-oxidative stresses and detoxification, is implicated in chemoresistance in several cancers. The functional roles of NRF2 in myeloid-derived suppressor cells and multiple myeloma cells, and the potential of targeting NRF2 for overcoming microenvironment-mediated drug resistance in multiple myeloma are also discussed.

scholarly journals APRIL and BCMA promote human multiple myeloma growth and immunosuppression in the bone marrow microenvironment

Blood ◽  
2016 ◽  
Vol 127 (25) ◽  
pp. 3225-3236 ◽  
Author(s):  
Yu-Tzu Tai ◽  
Chirag Acharya ◽  
Gang An ◽  
Michele Moschetta ◽  
Mike Y. Zhong ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Drug Resistance ◽  
Bone Marrow Microenvironment ◽  
Key Points ◽  
Human Multiple Myeloma

Key Points APRIL/BCMA activation promotes MM proliferation, survival, and immunosuppression in vitro and in vivo. Targeting the APRIL/BCMA pathway represents a promising mechanism-based immunotherapy to target MM and overcome drug resistance.

scholarly journals Mesenchymal stem cells from bone marrow regulate invasion and drug resistance of multiple myeloma cells by secreting chemokine CXCL13

2019 ◽  
Author(s):  
Guihua Zhang ◽  
Faan Miao ◽  
Jinge Xu ◽  
Rui Wang
Keyword(s):  
Stem Cells ◽  
Multiple Myeloma ◽  
Bone Marrow ◽  
Drug Resistance ◽  
Mesenchymal Stem Cells ◽  
Western Blot ◽  
Plasma Cells ◽  
Bone Marrow Microenvironment ◽  
Protein Expressions ◽  
Mdr 1

Multiple myeloma (MM) is a hematologic cancer arising from plasma cells. Mesenchymal stem cells (MSCs) are a heterogeneous cell population in the bone marrow microenvironment. In this study, we evaluated the regulatory effects of MSCs on the invasion and drug resistance of MM cells U266 and LP-1. Bone marrow samples from MM patients and normal subjects were collected. MSCs were extracted from bone marrow and cultured, and their phenotypes were identified by flow cytometry. The level of CXCL13 in the supernatant of cultured MSCs was detected by ELISA. The protein expression of CXCR5 (a specific receptor of CXCL13) in U266 and LP-1 cells was detected by Western blot. The effects of MSCs on the invasion of U266 and LP-1 cells and the resistance to bortezomib were assessed by Transwell and CCK-8 assay, respectively. The mRNA and protein expressions of BTK, NF-κB, BCL-2, and MDR-1 were detected by RT-PCR and Western blot, respectively. CXCL13 was secreted by MSCs in the bone marrow microenvironment, and the level in MSCs from MM patients was significantly higher than that of healthy subjects. CXCR5 was expressed in both U266 and LP-1 cells. The resistance of MM cells to bortezomib was enhanced by MSCs through CXCL13 secretion. The invasion and proliferation of U266 and LP-1 cells were promoted, and the mRNA and protein expressions of BTK, NF-κB, BCL-2, and MDR-1 were upregulated by MSCs. The basic biological functions of MM cells U266 and LP-1 were affected by MSCs via the CXCL13-mediated signaling pathway. This study provides valuable experimental evidence for clinical MM therapy.

scholarly journals Establishment of Cell Lines from Both Myeloma Bone Marrow and Plasmacytoma: SNU_MM1393_BM and SNU_MM1393_SC from a Single Patient

2014 ◽  
Vol 2014 ◽  
pp. 1-8 ◽  
Author(s):  
Youngil Koh ◽  
Woo-June Jung ◽  
Kwang-Sung Ahn ◽  
Sung-Soo Yoon
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Cell Lines ◽  
Mononuclear Cells ◽  
Cultured Cells ◽  
Clonal Evolution ◽  
Myeloma Cell ◽  
Mouse Bone Marrow ◽  
Single Patient ◽  
U266 Cell

Purpose.We tried to establish clinically relevant human myeloma cell lines that can contribute to the understanding of multiple myeloma (MM).Materials and Methods.Mononuclear cells obtained from MM patient’s bone marrow were injected via tail vein in an NRG/SCID mouse. Fourteen weeks after the injection, tumor developed at subcutis of the mouse. The engraftment of MM cells into mouse bone marrow (BM) was also observed. We separated and cultured cells from subcutis and BM.Results.After the separation and culture of cells from subcutis and BM, we established two cell lines originating from a single patient (SNU_MM1393_BM and SNU_MM1393_SC). Karyotype of the two newly established MM cell lines showed tetraploidy which is different from the karyotype of the patient (diploidy) indicating clonal evolution. In contrast to SNU_MM1393_BM, cell proliferation of SNU_MM1393_SC was IL-6 independent. SNU_MM1393_BM and SNU_MM1393_SC showed high degree of resistance against bortezomib compared to U266 cell line. SNU_MM1393_BM had the greater lethality compared to SNU_MM1393_SC.Conclusion.Two cell lines harboring different site tropisms established from a single patient showed differences in cytokine response and lethality. Our newly established cell lines could be used as a tool to understand the biology of multiple myeloma.

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