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 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 CD4+ T-cell killing of multiple myeloma cells is mediated by resident bone marrow macrophages

2020 ◽  
Vol 4 (12) ◽  
pp. 2595-2605 ◽  
Author(s):  
Ole Audun W. Haabeth ◽  
Kjartan Hennig ◽  
Marte Fauskanger ◽  
Geir Åge Løset ◽  
Bjarne Bogen ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
T Cells ◽  
T Cell ◽  
Cd4 T Cells ◽  
Antigen Presenting Cells ◽  
Bone Marrow Microenvironment ◽  
Cd4 T Cell ◽  
Myeloma Cells ◽  
Antigen Presenting

Abstract CD4+ T cells may induce potent antitumor immune responses through interaction with antigen-presenting cells within the tumor microenvironment. Using a murine model of multiple myeloma, we demonstrated that adoptive transfer of idiotype-specific CD4+ T cells may elicit curative responses against established multifocal myeloma in bone marrow. This finding indicates that the myeloma bone marrow niche contains antigen-presenting cells that may be rendered tumoricidal. Given the complexity of the bone marrow microenvironment, the mechanistic basis of such immunotherapeutic responses is not known. Through a functional characterization of antitumor CD4+ T-cell responses within the bone marrow microenvironment, we found that killing of myeloma cells is orchestrated by a population of bone marrow–resident CD11b+F4/80+MHC-IIHigh macrophages that have taken up and present secreted myeloma protein. The present results demonstrate the potential of resident macrophages as powerful mediators of tumor killing within the bone marrow and provide a basis for novel therapeutic strategies against multiple myeloma and other malignancies that affect the bone marrow.

Targeting the Serine-Threonine Kinase PIM2: Implications in IL-6 Mediated Survival in Myeloma

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3401-3401
Author(s):  
Jayakumar R Nair ◽  
Tyger L Howell ◽  
Justin Caserta ◽  
Carmen M Baldino ◽  
Gerald Fetterly ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Drug Resistance ◽  
Cell Death ◽  
Plasma Cells ◽  
Serine Threonine Kinase ◽  
Myeloma Cells ◽  
Threonine Kinase ◽  
Equity Ownership ◽  
Microarray Expression

Abstract Despite major advances in chemotherapy, multiple myeloma remains incurable and in need of new therapies that target novel pathways. Insufficient understanding of the molecular pathways that regulate survival in myeloma is a major impediment towards designing better therapies to prolong survival in patients or even cure the disease. This necessitates the identification of new protein targets that are crucial for the growth and survival of multiple myeloma. Just like normal plasma cells, MM cells also depend on their interactions with bone marrow stromal cells (BMSC) for survival and production of essential growth factors. We have previously shown that MM cells interact with dendritic cells (DC) in the microenvironment and in vitro can stimulate DC to produce IL-6 (ASH2010#132, ASH2011 #147, ASH2012#722). Our recent publications show that when MM cells are not in direct contact with DC, the IL-6 produced by DC can protect MM cells against dexamethasone induced cell death, while neutralizing the IL-6 with antibodies can reverse that effect (Nair et al., 2011). Unfortunately, exactly how this survival response is mediated in MM is not very clear. PIM2, a serine threonine kinase, part of the proto-oncogene group of PIM kinases has been implicated in survival in several types of cancers including prostate cancer and multiple myeloma. In our lab, microarray gene expression analysis of publicly available datasets (Figure 1) show a trend towards increased expression of PIM2 in plasma cells from myeloma patients (left panel), and significantly in the poor prognosis subgroup MAF (Zhan et al., 2006) (right panel). For the first time we show that IL-6 produced by DC may be protecting myeloma cells by up regulating PIM2 and inactivating a major protein translation inhibitor 4EBP1, which also happens to be a PIM2 target. We show that silencing PIM2 with siRNA down regulates PIM2 activity and reverses the inactivation of 4EBP1, while the latter is known to cause cell death in myeloma. We also demonstrate that neutralizing IL-6 in MM cells that either don’t produce IL-6 on their own (MM.1S) or those that do (U266), abrogates extraneous DC-IL6 ability to induce PIM2 and its downstream target 4EBP1. Recombinant IL-6 also provided similar induction of PIM2 in myeloma and increased 4EBP1 phosphorylation, which was again reversed by neutralizing the antibody against IL-6. In myeloma patients, the use of dexamethasone in frontline therapies is often complicated by the ability of the bone marrow environment to produce IL-6 that not only induce increased proliferation of MM but also help resist dexamethasone mediated cell death in myeloma. Interestingly, when we used a novel PIM2 inhibitor, JP_11646 (kindly provided by Jasco Pharmaceuticals, LLC), it not only arrested IL-6 induced proliferation even at sub-lethal doses, but also prevented IL-6 mediated rescue of myeloma cells (Figure 2). This suggests that PIM2 might be a major player in IL-6 mediated drug resistance in myeloma and targeting it may help to subvert IL-6 mediated survival in myeloma. Through RT-PCR and westerns, we also show that IL-6 modulates PIM2 expression and activity resulting in increased 4EBP1 phosphorylation (Figure 3). This was abrogated when PIM2 activity was inhibited by JP_11646 (Figure 3). We also present data that suggests IL-6 via PIM2 may be regulating other anti-apoptotic molecules downstream of IL-6 receptors including MCL-1, that is vital to MM survival. Developing PIM2 targeted therapies provides an exciting opportunity to affect the myeloma tumor microenvironment where MM induced IL-6 production from BM could be inducing drug resistance. Figure 1: Microarray expression ofPIM2 in myeloma and MAF Figure 1:. Microarray expression ofPIM2 in myeloma and MAF Figure 2: PIM2 inhibition abrogates IL-6 induced MM proliferation (A) and protection (B). Figure 2:. PIM2 inhibition abrogates IL-6 induced MM proliferation (A) and protection (B). Figure 3: Inhibiting PIM2 activity prevents PIM2 induced phosphorylation of 4EBP1 by IL-6 in myeloma Figure 3:. Inhibiting PIM2 activity prevents PIM2 induced phosphorylation of 4EBP1 by IL-6 in myeloma Disclosures Caserta: Jasco Pharmaceuticals LLC: Equity Ownership. Baldino:Jasco Pharmaceuticals LLC: Equity Ownership.

Bone Marrow Stroma Protects Myeloma Cells from Cytotoxic Damage Via Induction of the Oncoprotein MUC1

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3378-3378
Author(s):  
Michal Bar-Natan ◽  
Katarina Luptakova ◽  
Maxwell Douglas Coll ◽  
Dina Stroopinsky ◽  
Hasan Rajabi ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Drug Resistance ◽  
Cell Viability ◽  
Cell Line ◽  
Stromal Cells ◽  
Stromal Cell ◽  
Fold Increase ◽  
Bone Marrow Microenvironment ◽  
Muc1 Expression ◽  
Myeloma Cells

Abstract Introduction : Stromal cells in the bone marrow microenvironment of patients with multiple myeloma (MM) are thought to play a vital role in promoting cell growth and protection from cytotoxic injury. Targeting of stromal-myeloma cell interactions to enhance anti-myeloma treatment represents a promising therapeutic strategy. The MUC1 oncoprotein is a critical oncoprotein that is expressed in the majority of primary myeloma cells and regulates downstream pathways such as NFkB and β-catenin/wnt that modulate myeloma growth and survival. Inhibition of MUC1 via a cell penetrating peptide (GO-203) that blocks down stream signaling reverses resistance to bortezomib (BZT). Herein we studied the influence of bone marrow stromal cells (BMSC) on MUC1 expression on MM cells, and its link to drug resistance. Methods and Results : Coculture of MM human cell lines (RPMI and U266) with a stromal cell line (HS-5), resulted in an upregulation of MUC1 expression as determined by an approximately 2 fold increase in the mean fluorescent intensity (MFI) of MUC1 as measured by flow cytometry. Similar findings were observed following coculture of MM cells with stromal cells isolated from primary bone marrow mononuclear cells (BMSC) of MM patients. Stromal cell mediated upregulation of MUC1 expression was subsequently confirmed by Western blot analysis. Patient derived MM cells were also noted to increase their MUC1 expression 2.9 fold when co-cultured with stroma (HS-5 cell line). MUC1 expression was also increased following coculture of MM cells with stromal cells in transwell plates, suggesting the effect was mediated by soluble factors not requiring cell-cell contact. Consistent with these findings, we demonstrated that addition of recombinant IL-6, a stromal cell derived cytokine, to MM cells resulted in a 2 fold increase in MFI of MUC1 expression. Moreover, coculture of MM cells with IL-6 neutralizing antibodies abrogated the effect of BMSC on MUC1 expression. These results suggest that stromal cell secretion of IL-6 plays a role in upregulation of the oncoprotein MUC1 on MM cells. We subsequently evaluated the effect of stromal cell induction of MUC1 expression on resistance to anti-myeloma agents. Increased MUC1 expression following coculture of MM cells with BMSC was associated with a higher level of resistance to BTZ (20nM), resulting in 48% less cell death by CellTiter-Glo and annexin/propidium iodide (PI) staining. Conversely, we demonstrated that silencing of MUC1 expression using a lentiviral siRNA resulted in enhanced sensitivity to anti-myeloma agents. Cell viability in MUC1 silenced as compared to wild type RPMI cells decreased by 18%, 43%, and 50% when treated with 10mg/ml cyclophosphamide (Cy), 5nM BZT, and 0.1mM melphalan, respectively. MUC1 silenced U266 cells demonstrated a decrease in cell viability by 24%, 34%, and 45% when treated with 10mg/ml Cy, 5nM BZT, and 1mM lenalidomide respectively. Similarly, exposure of primary MM cells to the MUC1 inhibitor GO-203 resulted in enhanced MM cell sensitivity to bortezomib and cyclophosphamide evidenced by a 60% and 39% decrease in cell viability respectively, compared to each drug alone. Conclusions : Our results delineate one of the mechanisms by which the bone marrow microenvironment confers drug resistance in MM. MM cells co-cultured with BMSC have enhanced expression of MUC1, mediated by IL-6 secretion. Overexpression in turn confers MM cell resistance to standard anti-myeloma agents. Importantly inhibition of MUC1 via silencing of expression or exposure to a small molecule inhibitor can overcome drug resistance to known anti-myeloma drugs, providing the rationale for clinical evaluation of combination therapy. Disclosures Kufe: Genus Oncology: Consultancy, Equity Ownership.

The IL-6 receptor antagonist SANT-7 overcomes bone marrow stromal cell-mediated drug resistance of multiple myeloma cells

2001 ◽  
Vol 93 (5) ◽  
pp. 674-680 ◽  
Author(s):  
Dirk H�nemann ◽  
Manik Chatterjee ◽  
Rocco Savino ◽  
Kurt Bommert ◽  
Renate Burger ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Drug Resistance ◽  
Receptor Antagonist ◽  
Stromal Cell ◽  
Bone Marrow Stromal Cell ◽  
Myeloma Cells ◽  
Marrow Stromal Cell

Angiogenesis in Multiple Myeloma (MM): Angiogenic Switch or Reflexion of Plasma Cell Number? A Gene Expression Based Survey in Primary Myeloma Cells and the Bone Marrow Microenvironment.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3405-3405
Author(s):  
Dirk Hose ◽  
John DeVos ◽  
Christiane Heiß ◽  
Jean-Francois Rossi ◽  
Angela Rösen-Wolff ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Plasma Cell ◽  
Empirical Bayes ◽  
Plasma Cells ◽  
De Novo ◽  
Cell Number ◽  
Bone Marrow Microenvironment ◽  
Myeloma Cells ◽  
Angiogenic Switch

Abstract BACKGROUND. Angiogenesis is a hallmark of active multiple myeloma. However, two etiologic hypotheses have been proposed: an angiogenic switch (i.e. differential or de novo expression of pro/antiangiogenic genes in MM), and, alternatively an effect of increased plasma cell number. AIM of this study was to investigate the angiogenic signature of multiple myeloma cells (MMC), normal bone marrow plasma cells (BMPC), the bone marrow microenvironment (BMME) and cellular subfractions therein. PATIENTS AND METHODS. 128 newly diagnosed MM-patients (65 training (TG) / 63 independent validation group (VG)) and 14 normal donors (ND) were included. Bone marrow aspirates were CD138-purified by activated magnetic cell sorting. Whole bone marrow (n=49) and FACSAria sorted subfractions thereof (n=5) were investigated. RNA was in-vitro transcribed and hybridised to Affymetrix HG U133 A+B GeneChip (TG) and HG U133 2.0 plus arrays (VG). Expression data were gcrma-normalised and the empirical Bayes algorithm used. p-Values were adjusted using the Benjamini-Hochberg method (Bioconductor). iFISH was performed on purified MM-cells using probesets for chromosomes 1q21, 9q34, 11q23, 11q13, 13q14, 15q22, 17p13, 19q13, 22q11 and the translocations t(4;14) and t(11;14). HGF expression was verified by real time RT-PCR and western blotting. Based on Medline review, we established a list of 89 pro- and 56 antiangiogenic genes and investigated their expression according to the stage of disease: BMPC vs. MGUS, SD stage I (asymptomatic myeloma) vs. SD stage II/III (symptomatic myeloma requiring therapy). RESULTS. BMPC express pro- (e.g. VEGFA) and antiangiogenic genes (e.g. TIMP2). Only one pro-angiogenic gene (hepatocyte growth factor, HGF) is significantly overexpressed in MMC compared to BMPC. HGF has previously been linked with myeloma progression and induction of angiogenesis. Six antiangiogenic genes (TIMP2, SERPINF1, COL18A1, PF4, THBS1, CXCL14) are downregulated in MMC compared with BMPC. Compared to healthy donors, the BMME of MM shows a significant downregulation of PLAU (urokinase, antiangiogenic) and upregulation of TNF(proangiogenic). CONCLUSION. Upregulation of HGF-expression, downregulation of TIMP2, SERPINF1, COLA18A1, PF4, THBS1 and CXCL14 expression in MMC as well as downregulation of PLAU and upregulation of TNFα in the BMME seem to indicate an “angiogenic switch”. However, given the relatively low number of differentially expressed genes (7/145) and the expression of angiogenic genes by BMPC, an effect caused by an increasing number of plasma cells might be evenly important.

Adipocyte Fatty Acid Binding Protein Promotes Multiple Myeloma through Regulating Bone Marrow Microenvironment

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 31-32
Author(s):  
Lingling Shu ◽  
Jinyuan Li ◽  
Weida Wang ◽  
Xiaoping Wu ◽  
Hanying Huang ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Fatty Acid ◽  
Lipid Metabolism ◽  
Fatty Acid Binding Protein ◽  
Binding Protein ◽  
Bone Marrow Microenvironment ◽  
Fatty Acid Binding ◽  
Myeloma Cells ◽  
Acid Binding Protein

Multiple myeloma (MM) is a plasma cell malignancy in bone marrow, which often occurs in middle-aged and elderly people and also obese patients. Aging and obesity can lead to the ectopic accumulation of adipocytes in bone marrow, which can cause the change of bone marrow microenvironment. Bone marrow adipocyte (BMA) displays distinct immune regulatory properties rather than provides energy substrates. Despite BMA accounts for 70% of the entire volume of bone marrow microenvironment, while the mechanisms still remain elusive. The present study aims to investigate the precise mechanism of BMA promoting myeloma pathogenesis and new potential therapeutic strategies targeting bone marrow microenvironment. Newly diagnosed MM patients and their relative healthy control in our cancer center were recruited. We found that the quantity of BMA increased significantly in multiple myeloma patients, accompanied with the elevated level of adipocyte fatty acid binding protein (A-FABP) by flow cytometry and immunohistochemistry staining. A-FABP is a fatty acid chaperone, which abundantly expressed in adipocytes, playing a critical role in lipid metabolism and immune response. To further explore the role of A-FABP in the pathogenesis of MM, A-FABP knockout (KO) mice and their wide type (WT) littermates were employed and fed with stand chow or high fat diet (HFD). Tumor burden and MM-related osteolytic lesions were significantly lower in A-FABP KO mice comparing to their WT littermates fed with HFD. It was observed that A-FABP deficiency did not change the content of BMA in bone marrow, but cytokines levels in bone marrow such as TNFα, IL-6, RANKL, DPP4 were significantly reduced. The infiltration and pro-inflammatory polarization (M1/M2) of macrophages (MΦ) decreased significantly. Moreover, A-FABP promotes the expression of Th1 and Th17 cells, while the percentage of Th2 and Treg cells are significantly declined. Furthermore, pharmacological inhibition of A-FABP by administration BMS309403 also alleviates the invasion and metastasis of MM in mouse. In addition, co-culture of myeloma cells with pharmacological inhibition or genetic depletion of A-FABP in adipocytes significantly decreased the uptake of free fatty acid and oxygen consumption of myeloma cells. In conclusion, A-FABP increased in BMA in response to aging or obesity, remodeled the energy and lipid metabolism of myeloma cells, and manipulated bone marrow microenvironment to a pro-tumor environment, promoting the proliferation and migration of myeloma cells. This study will shed light on the potential of A-FABP specific inhibitor BMS309403 as the therapeutic strategy of multiple myeloma targeting bone marrow microenvironment. Disclosures No relevant conflicts of interest to declare.

Higher Expression Levels of the Adhesion Molecules VLA-4 and ICAM-1 on Multiple Myeloma Cells after Chemotherapy Are Associated with Survival of a Multidrug Resistant Subpopulation in Vivo.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 4866-4866
Author(s):  
Ralf Schmidmaier ◽  
Kerstin Mörsdorf ◽  
Philipp Baumann ◽  
Bertold Emmerich ◽  
Gerold Meinhardt
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Drug Resistance ◽  
Adhesion Molecules ◽  
Stromal Cells ◽  
High Dose ◽  
Myeloma Cells ◽  
Expression Levels ◽  
Before And After ◽  
Primary Drug

Abstract Objectives: Primary drug resistance is a major problem in multiple myeloma (MM), an incurable disease of the bone marrow. Adhesion of multiple myeloma cells to bone marrow stromal cells (BMSC) has been shown to cause strong primary resistance. The adhesion molecules LFA-1 and VLA-4 are upregulated upon treatment with cytotoxic agents. Furthermore, we have shown that the corresponding ligands on HS-5 BMSCs, VCAM-1 and ICAM-1, are upregulated after incubation with melphalan, suggesting increase of adhesion mediated drug resistance after chemotherapy. In this context, the expression levels of important adhesion molecules on MM cells of consecutive MM patients before and after chemotherapy have been determined in this study. Methods: The expression levels of VLA-1, VLA-4, VLA-5, LFA-1, VCAM, ICAM-1, CD138, CD38, and CD56 were determined on MM cell lines, HS-5 stromal cells, and primary myeloma cells of 20 consecutive patients by flow cytometry in comparison to isotype control. 9 patients had been pre-treated (mostly induction chemotherapy and high dose melphalan with stem cell rescue) and 11 patients had been at diagnosis without treatment. Interpatient comparison of treated and untreated patients was performed. Intrapatient analysis (before and after high dose chemotherapy) will be performed in the follow up. Results: VLA-4 and ICAM-1 are upregulated after chemotherapy by 54% and 64%, respectively. Similar upregulation of CD38 could be observed (62%), whereas CD138 shows downregulation by about 50%. CD56, VCAM, and LFA-1 expression was not significantly altered after chemotherapy. Conclusion: The adhesion molecules VLA-4 and ICAM-1, which are essential for MM-BMSC interaction, are upregulated after chemotherapy. This finding supports our preclinical data and the hypothesis, that adhered, primary drug resistant MM cells are selected by chemotherapy and herewith contribute to multidrug resistance in multiple myeloma.

Influence of Targeted Therapy in Redefining High-Risk Myeloma.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. sci-7-sci-7
Author(s):  
Lori Hazlehurst ◽  
William S. Dalton ◽  
Danielle Yarde ◽  
Yulia Nefedova ◽  
Dmitry Gabrilovich
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Drug Resistance ◽  
Clinical Trials ◽  
Cell Adhesion ◽  
Tumor Microenvironment ◽  
Residual Disease ◽  
Myeloma Cell ◽  
Myeloma Cells ◽  
Acquired Drug Resistance

Abstract Multiple myeloma is a disease that typically responds to initial treatment; however, the disease is not cured by chemotherapy, and drug resistance ultimately develops. Most studies investigating the problem of drug resistance have focused on acquired resistance or resistance that occurs after response to prior therapy as a result of residual disease. Intrinsic factors, such as reduced drug uptake, enhanced damage response (i.e., DNA repair), altered drug metabolism, or inhibition of programmed cell death pathways are known to contribute to acquired drug resistance. For example, it was recently reported that the acquired melphalan resistant phenotype in myeloma cell lines was associated with over-expression of the Fanconi anemia (FA)/BRCA pathway genes. Enhanced interstrand cross-link (ICL) repair via the FA/BRCA pathway was causally related to melphalan resistance and disruption of this pathway using knock-down techniques reversed drug resistance. Furthermore, bortezomib (Velcade) has been reported to enhance melphalan treatment, and recent pre-clinical data has shown that bortezomib reduces FA/BRCA gene expression and function. Clinical trials are necessary to determine the role of the FA/ BRCA pathway in acquired drug resistance for myeloma patients and whether targeting this pathway enables prevention of or the ability to overcome acquired melphalan resistance in myeloma patients. Conversely, factors that promote tumor cell survival and drug resistance that are external to the tumor cell itself might exist. Evidence supporting the importance of understanding the influence of the tumor microenvironment on drug sensitivity has been reported by several investigators. The tumor microenvironment for hematologic malignancies, including myeloma, is principally the bone marrow. The bone marrow contains candidate components that contribute to reduced drug activity, minimal residual disease, and emergence of drug resistant cells. Cell adhesion molecules expressed by myeloma cells, including the β integrins, bind to fibronectin and other extracellular matrix components of the bone marrow, and this interaction contributes to a reversible, de novo drug resistance phenotype called “cell adhesion mediated drug resistance” or CAMDR. Adhesion via integrins is known to activate a network of signal transduction pathways that influence cell survival, growth, and differentiation. Several targets that are influenced by integrin adhesion and may contribute to CAM-DR include the following: reduced proapoptotic Bim levels, alterations in nuclear topoisomerase II levels, increased p27 kip1 levels, and changes in FLIP1 levels. In addition, myeloma cell adhesion to bone marrow stroma (BMS) involves other adhesion molecules and signaling events that promote CAMDR. For example, Notch1 receptors expressed on multiple myeloma cells when stimulated by Jagged causes growth arrest and protection from drug-induced apoptosis. Recently, approaches to inhibit integrin and Notch signaling associated with CAM-DR have been examined pre-clinically. Clinical trials are necessary to determine if these approaches will prevent or overcome CAM-DR in patients.

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