Bortezomib-Induced Reversal of CAM-DR Phenotype in Myeloma Is Associated with AKT and ERK1/2 Signaling.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 3357-3357
Author(s):  
Ramadevi Nimmanapalli ◽  
Lori Hazlehurst ◽  
Steven Enkemann ◽  
Melissa Alsina ◽  
William S. Dalton
Keyword(s):  
Multiple Myeloma ◽  
Drug Resistance ◽  
Tumor Cell ◽  
Expression Profiles ◽  
Specific Inhibitor ◽  
Gene Expression Profiles ◽  
Akt Signaling ◽  
Chemotherapeutic Agents ◽  
Dependent Manner ◽  
Myeloma Cells

Abstract An increasing body of evidence suggests that interactions between myeloma cells and the microenvironment are critical for tumor cell survival, proliferation and drug resistance. These pro-survival interactions include binding of soluble factors, and direct contact with stromal cells, or extra cellular matrix (ECM) components such as fibronectin (FN). More specifically, adhesion of multiple myeloma (MM) to FN via ν1 integrins has been demonstrated to confer resistance to a host of chemotherapeutic agents (Shain et al., 2000). This anti-apoptotic phenomenon, termed cell adhesion-mediated drug resistance (CAM-DR), is an intrinsic pathway for evading the therapy-induced apoptosis (Damiano et al., 2000). Bortezomib (PS-341), a specific inhibitor of proteosome, has been shown to cause apoptosis of several tumor cell lines including multiple myeloma. In contrast to conventional cytotoxics, Bortezomib, showed more apoptosis in 24 hours for 8226 myeloma cells adhered to FN (25 % 10 nM) compared to cells in suspension (10 % 10 nM) in a dose -dependent manner. To investigate the signal transduction mechanism responsible for the reversal of CAM-DR phenotype by Bortezomib, we conducted Affymetrix GeneChipÒ Expression of 8226 cells cultured either in suspension, or adhered to FN in the presence and absence of Bortezomib (50 nM) for 4 and 24 hours using the Affymetrix U133A chips. A total of 197 genes were upregulated on FN compared to suspension, among which only 12 genes were increased with Bortezomib and 105 genes were decreased with PS-341. A total of 870 genes were downregulated on FN adhesion, among which the majority of them were increased with Bortezomib. Similar patterns of gene expression profiles were observed after 24 hrs of treatment with Bortezomib. To examine how Bortezomib is reversing CAMDR phenotype, we chose to examine the genes that were changed with FN adhesion and reversed when treated with Bortezomib. The adhesion of 8226 cells to FN enhanced both ERK1/2 and AKT signaling pathways, and both pathways were down regulated when treated with Bortezomib. The main indicators of the AKT signaling on FN are upregulation of PYK2, AKT2, MDM2 and downregulation of p21 and BAD. In conformation with our micro-array data, PYK2 phosphorylation and ERK1/2 phosphorylation were enhanced when 8226 cells were adhered to FN. The mechanisms to understand role of PYK2 phosphorylation and downstream AKT signaling in Bortezomib-induced reversal of CAMDR are under investigation.

The IGF1-R Inhibitor AEW541 Is a Potent Anti-Myeloma Agent That Overcomes Drugs Resistance, and Has Synergistic Activity with Other New Drugs.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2599-2599
Author(s):  
Patricia Maiso ◽  
Enrique M. Ocio ◽  
Mercedes Garayoa ◽  
Mark A. Pearson ◽  
Atanasio Pandiella ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Cycle ◽  
Cell Death ◽  
Expression Profiles ◽  
Chemotherapeutic Agents ◽  
Mitochondrial Outer Membrane ◽  
Late Time ◽  
Synergistic Activity ◽  
Dependent Manner ◽  
Myeloma Cells

Abstract Multiple myeloma (MM) represents an incurable disease for which development of new therapies is required. Here we report the effect on myeloma cells of AEW541, a new small molecule, belonging to the pyrrolo[2,3-d] pyrimidine class, identified as inhibitor of the IGF-1R in vitro kinase activity. AEW541 showed a potent antimyeloma activity (IC50 <4.5 μM) on MM cell lines both sensitive (MM1S, U266, OPM2, RPMI8226) and resistant (MM1R and U266LR7) to conventional chemotherapeutic agents. In fresh cells from five MM patients a marked antitumor activity was confirmed. AEW541 showed a synergistic effect with dexamethasone and lenalidomide, while it was additive with melphalan and bortezomib. Moreover the triple combination of AEW541, bortezomib and dexamethasone showed even higher anti-MM activity. Gene expression profiles of MM1S cells identified a total of 967 genes to be significantly deregulated (transcriptional changes in gene expression of 2-fold or greater) by treatment with AEW541. The classification of these genes according to functional categories indicated that 3.5% were involved in apoptosis/responses to stress and 13% in the control of cell cycle/proliferation. By Western analyses, we observed that AEW541 affected genes involved in cell cycle and cell death pathways. AEW541 blocked cell cycle progression, and this was accompanied by p27, up-regulation and pRb, CCND1, CCNA and CCNE downregulation. AEW541 induced cell death through an increase in the mitochondrial outer membrane permeability and provoked DNA fragmentation. AEW541 induced apoptosis and at late time points, also activated caspases 8,9 and 3. The pan-caspase inhibitor Z-VAD-FMK only slightly decreased the sensitivity to AEW541. In addition, AEW541 stimulated a caspase-independent pathway, through the release of AIF and Endonuclease G from the mitochondria. It is therefore conceivable that both caspase dependent and independent pathways are activated by AEW541 in MM cells, although the effect of AEW541 on cell cycle arrest is an earlier and more potent event. Finally, AEW541 was able to overcome the protective effect that confers IL-6, IGF-1 and BMSCs to myeloma cells in a dose dependent manner. All these data indicate that AEW541 could be a useful drug for the treatment of MM patients, particularly in combination with other novel agents such as bortezomib or lenalidomide together with dexamethasone.

AKT Dependent and AKT Independent Multiple Myeloma: Heterogeneity in Tumor Cell Signaling.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1511-1511
Author(s):  
Angela Zöllinger ◽  
Thorsten Stühmer ◽  
Manik Chatterjee ◽  
Ralf C. Bargou
Keyword(s):  
Multiple Myeloma ◽  
Tumor Cell ◽  
Cell Line ◽  
Cell Lines ◽  
Specific Inhibitor ◽  
Akt Signaling ◽  
Akt Pathway ◽  
Special Role ◽  
Phosphorylated Akt ◽  
Pharmacologic Inhibition

Abstract The PI3K/Akt pathway has been reported to critically contribute to survival and malignant growth of multiple myeloma (MM). Because most of these data are based on pharmacologic inhibition it is not clear if the effects are due to Akt inhibition or off-target effects. Furthermore, the Akt family of kinases consists of three highly homologous isoforms, that may, nonetheless, display individual functional properties. We therefore conducted siRNA experiments to evaluate if any single isoform posesses a special role for the viability of MM cells. This was complemented with extensive analyses into the functional and signaling properties of the Akt pathway in primary MM cells (n = 30). Our knock-down experiments revealed that in MM.1S, an MM cell line with constitutive phospho-Akt signaling, Akt1 and Akt2 both contributed to MM cell survival whereas Akt3 seemed to be of less relevance. Conversely, survival of MM cell line AMO-1 which has no constitutive phospho-Akt signal was completely unaffected. Treatment of these MM cell lines with the Akt1 and Akt2 specific inhibitor Akti-1/2 showed that this drug totally abolished the phospho-Akt signal in MM.1S at a concentration of 10 microM. Again, MM.1S cells underwent apoptosis whereas AMO-1 cells were resistant. Next, we analyzed Akt signaling in a large panel of primary MM samples. Phosphorylated Akt was determined with intracellular staining and flow cytometry analysis in primary tumor samples and could be detected in about 60% of MM cases. This constitutive signal could be blocked with Akti-1/2 in the presence and absence of bone marrow stromal cells. Pharmacologic inhibition of Akt led to strong induction of cell death in 46% of primary MM samples, whereas the rest was largely resistant to Akt inhibition. The samples sensitive to Akt inhibition were mostly identical to those that displayed a constitutive phospho-Akt signal. Of interest, there was no correlation between Akt dependence and mutational inactivation of PTEN. Further inhibition of other signaling cascades implicated in growth and survival of MM cells, such as the MAPK or STAT3 pathways, had only minor additional effects on tumor cell viability of samples resistant to Akt inhibition. Our analysis indicates substantial heterogeneity in MM cells that defines Akt dependent and Akt independent MM subgroups. Akt1 and Akt2 proved relevant for the survival of subsets of MM cell lines and primary samples. Taken together, this is the first comprehensive functional and molecular signaling analysis of primary MM samples which led to the identification of novel functionally defined myeloma subgroups.

scholarly journals NEK2 Inhibition Enhances the Efficacy of PD-1/PD-L1 Blockade in Multiple Myeloma

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 2671-2671
Author(s):  
Yan Cheng ◽  
Fumou Sun ◽  
Huojun Cao ◽  
Dongzheng Gai ◽  
Bailu Peng ◽  
...  
Keyword(s):  
Gene Expression ◽  
Multiple Myeloma ◽  
B Cells ◽  
Cell Lines ◽  
Immune Checkpoint ◽  
Mononuclear Cells ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Gene Set Enrichment Analysis ◽  
Myeloma Cells

Abstract Introduction The development of new treatments for high-risk multiple myeloma (HRMM) are needed. The PD-1/PD-L1 axis is one of the chief inhibitory immune checkpoints in antitumor immunity. Despite the success of PD-1 (PDCD1) / PD-L1 (CD274) blockade in some neoplasms, use of it as a monotherapy has failed to improve outcome in RRMM. We have previously demonstrated that the cell-cycle-regulated serine-threonine kinase, NEK2 is elevated in HRMM and that inhibition of NEK2 can overcome drug-resistance and prolong survival of xenografted MM cells. Here, we aimed to investigate the possible role of NEK2 in regulating the immune checkpoint response in MM and development of possible anti-PD1/PDL1 combination therapies. Methods Gene expression profiles and pathway enrichment analyses were conducted on oligonucleotide microarray gene expression profiles from over 1000 primary MM samples to evaluate the correlation of NEK2 and immune checkpoint expression levels. To elucidate the underlying mechanism, we used Nek2 -/- mice crossed with EμMyc mice to generate B cell tumor mouse model with NEK2 deficiency. RNA-sequencing analyses of premalignant B cells was compared between EμMyc/Nek2 WT and EμMyc/Nek2 -/- mice. The hub molecular regulators in the NEK2 correlated pathways were further determined by western blot using NEK2 overexpressing and knockdown cell lines and then verified by co-immunoprecipitation with a NEK2 antibody. Lastly, to establish its clinic significance, the efficacy of INH1 (small compound NEK2 inhibitor), (D)-PPA 1 (peptide-based PD-1/PD-L1 interaction inhibitor) or a PD-L1 (monoclonal antibody) was tested in bone marrow BM mononuclear cells from primary MM patients in-vitro as well as in MM xenografts. Tumor burden and T cell immune responses were monitored by M-spike and mass cytometry. Results Gene expression profiles demonstrated that CD274 expression was significantly higher in the non-proliferative hyperdiploid (HY) subtype of MM, representing between 25-35% of all MM. NEK2 was negatively correlated with CD274 gene expression across all 7 MM subtypes. Gene set enrichment analysis showed that the IFN-γ signaling pathway, which can induce CD274 expression, was significantly enriched in the HY subtype as well as premalignant B cells from EμMyc/Nek2 -/- mice. Elevated expression of EZH2, a histone methyltransferase gene, is also highly correlated wirth NEK2 levels in primary MM. We found that NEK2 inhibition increases CD274 expression as well as reduced EZH2 expression and H3K27me3 levels in MM cell lines. In contrarst, myeloma cells overexpressing NEK2 showed increased expression and activity of EZH2 and H3K27me3 levels. Thus, NEK2 appears to regulate CD274/PD-L1 expression through EZH2-mediated histone methylation. Next we demonstrated that NEK2 and EZH2 directly interact and that overexpression of NEK2 leads to increased methylation of the CD274/PD-L1 gene. We treated BM mononuclear cells from primary MM with PD-1/PD-L1 inhibitor with and without a NEK2 inhibitor. The combination was most effective at eliminating CD138 + myeloma cells while having no effects on T, B and myeloid cell populations. Conclusion Our study showed that expression of CD274/PD-L1 is suppressed in primary HRMM and that CD274/PD-L1 expression is negatively regulated by NEK2 via EZH2-mediated methylation. Inhibition of NEK2 sensitizes myeloma cells to PD-1/PD-L1 blockade, showing either a synergistic or an additive effect in MM cell cytotoxicity. Disclosures No relevant conflicts of interest to declare.

Comparison of Newly Diagnosed and Relapsed Refractory Multiple Myeloma Using Transcriptional Profiling of Myeloma Cells.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1555-1555
Author(s):  
Shaji Kumar ◽  
Philip R. Greipp ◽  
Jessica L. Haug ◽  
Michael Kline ◽  
Wee Joo Chng ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Drug Resistance ◽  
Differential Expression ◽  
Median Survival ◽  
Plasma Cell ◽  
Plasma Cells ◽  
Expression Profiles ◽  
Significant Proportion ◽  
Newly Diagnosed ◽  
Myeloma Cells

Abstract Background: Multiple myeloma (MM) is a plasma cell malignancy that is incurable with current approaches. The median survival for patients with MM is around four years and a significant proportion of patients experience a course characterized by multiple relapses treated with different therapies. The median survival for patients relapsing after the initial therapy is nearly 18 months and successive treatment strategies result in decreasing response durations, likely reflecting acquired drug resistance. In order to better understand the biological changes associated with advanced, relapsed, refractory MM, we compared gene expression profiles (GEP) of malignant plasma cells isolated from patients with relapsed refractory MM and compared them to plasma cells from patients with newly diagnosed MM. Methods: In order to obtain two relatively homogenous group of patients, we compared samples from 44 patient with newly diagnosed MM enrolled in the ECOG E1A00 clinical trial (comparing thalidomide and dexamethasone to dexamethasone alone) to 44 patients with relapsed refractory MM enrolled in a phase II trial of Velcade (SUMMIT), where most patients had four or more previous relapses. Plasma cells from bone marrow aspirates were separated by magnetic bead selection of CD138 positive cells and studied using Affymetrix HG-U133A chips using standard methodology. The arrays were analyzed using Genespring 7.2 software following GCRMA normalization and genes with differential expression between the two datasets were examined. Differentially expressed genes were further analyzed using Ingenuity Pathways Analysis program. Results: A total of 864 genes were identified which were at least two fold and significantly different between the newly diagnosed and relapsed patients. Using Ingenuity software, 437 of these genes were mapped to different biological networks. Examination of the canonical pathways demonstrated several important cellular pathways differentially regulated between the two groups. Several important mediators of the cytokines, receptors and respective signaling pathways appear to be down regulated in the relapsed group and included IGF-1, HGF, SDF-1 alpha, gp130 and importantly the MEK/ERK pathway. Additionally expression of adhesion molecules such as VCAM1 and PECAM was decreased in the relapsed group compared to newly diagnosed pts. There appear to increased tissue hypoxia in the relapsed marrow as indicated by up regulation of HIF-1 alpha as well increased levels of Placental growth factor. Myeloma cells from relapsed disease were characterized by decreased expression of mcl1, FLIP1, and bcl-xL and increased caspase 8 relative to newly diagnosed group. Also seen was decreased expression of the glucocorticoid and interferon receptors in the relapsed setting. Conclusion: Comparison of the GEP between MM cells from newly diagnosed and relapsed pts demonstrates important differences that have potential biological relevance. The plasma cell in the relapsed setting appears to be more independent of the tumor microenvironment. Additionally, differential expression of some of the genes provides clues to mechanisms of drug resistance commonly observed in the relapsed pts. We are in the process of validating some of the key findings from these analyses.

Effect of Imids on Gene Expression Profiles of Fresh Human Myeloma Cells

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 5013-5013
Author(s):  
Ines Tagoug ◽  
Adriana Plesa ◽  
Julie Vendrell ◽  
Charles Dumontet
Keyword(s):  
Gene Expression ◽  
Multiple Myeloma ◽  
Family Member ◽  
Magnetic Beads ◽  
Expression Profiles ◽  
Calf Serum ◽  
Gene Expression Profiles ◽  
Differentially Expressed ◽  
Myeloma Cells ◽  
Human Myeloma Cells

Abstract Abstract 5013 Immunomodulatory drugs represent a major therapeutic advance in the treatment of patients with multiple myeloma. While these agents appear to exert various effects on the microenvironment, including effect on immune cells and angiogenesis, a direct effect on the tumor cells themselves is also likely. To describe and compare the effect of the three clinically available agents (thalidomide, lenalidomide, pomalidomide) we analyzed the gene expression profiles of fresh human myeloma cells exposed to thalidomide, lenalidomide or pomalidomide, using high density DNA arrays. Fresh human myeloma samples were obtained from bone marrow aspirates of patients with myeloma, and myeloma cells were immunopurified using anti CD138 magnetic beads. Purified myeloma cells (1.106 cells/ml) were incubated for 24 hours in RPMI 1640 medium supplemented with 10% fetal calf serum under each of the four following conditions: 1) DMSO; 2) thalidomide 40 microM; 3) lenalidomide 1 microM; 4) pomalidomide 100 nM. These levels are achievable in the plasma of MM pts. Pangenomic array experiments were performed usingWhole Human Genome 4 × 44K Agilent one-color microarrays. Data were normalized using the quantile normalization method. Samples were analysed for differentially expressed genes, taking into account both the level of significance and the fold-change. Ten evaluable samples were processed. Exposure to thalidomide, lenalidomide and pomalidomide induced differential expression of 36, 50 and 75 genes, respectively, in comparison to DMSO-exposed controls, the total list including 101 genes. Twelve of these were found to be differentially expressed after exposure to all of the three agents, including trophoblast glycoprotein, WAS protein family member 1, dickkopf homolog 1, pentraxin-related gene, CD28, interleukin 12B, tissue factor pathway inhibitor 2, phospholipase A2, dehydrogenase/reductase (SDR family) member 9, hypothetical LOC145788 and betacellulin. These commonly altered genes could be mechanistically involved in themultiple activities of these agents in multiple myeloma or may represent epiphenoma mechanistically unrelated to drug-induced cell death. Genes differentially expressed between the treatment with each of these agents could be indicative of the different and non-overlapping actions these agents have in multiple myeloma. An example of this is the recent demonstration that pomalidomide is clinically active in lenalidomide refractory patients. These results suggest that exposure to IMIDs induce various intracellular signalization pathways in myeloma cells which might be involved in the cytotoxic activity of these compounds. Disclosures: Dumontet: Celgene: Research Funding.

NALP7 and NALP11 Differential Expression Correlates with Glucocorticoid Sensitivity in Multiple Myeloma Cell Lines.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2366-2366
Author(s):  
Shuo Ma ◽  
Nancy L. Krett ◽  
Steven T. Rosen
Keyword(s):  
Multiple Myeloma ◽  
Differential Expression ◽  
Expression Profiles ◽  
Growth Arrest ◽  
Biological Significance ◽  
Pcr Analysis ◽  
Mrna Levels ◽  
Dependent Manner ◽  
Myeloma Cells ◽  
Transfected Cells

Abstract Multiple myeloma is the second most common hematological malignancy and remains incurable. Glucocorticoids (GC) are among the most commonly used therapy for myeloma by inducing growth arrest and apoptosis in myeloma cells. While GC treatments are usually effective at first, all patients will eventually develop resistance. Understanding the mechanism of GC resistance is an important step towards developing new therapy to overcome this significant clinical problem. In order to study the mechanism underlying the GC resistance phenotype in myeloma, we compared the gene expression profiles of the clinically relevant myeloma clones derived from the same patient (MM.1) which are either sensitive or resistant to GC-induced apoptosis and growth inhibition. By cDNA microarray analysis, we identified NALP7 and NALP11 among the few genes that showed most significant differential levels of expression between the sensitive and resistant myeloma lines. Both genes belong to the NALP (NATCH-, LRR- and pyrin domain-containing proteins) family of proteins which have been implicated in the innate immune response. However, their function and regulation in myeloma has never been explored. Using a two-step quantitative real-time RT-PCR analysis, we have demonstrated that the NALP7 expression was significantly reduced whereas the NALP11 expression was markedly increased in GC-resistant MM.1 cells compared to the GC-sensitive MM.1 cells. We then investigated the biological significance of NALP gene differential expression in myeloma GC-resistance. To test whether suppressing NALP7 expression would lead to GC-resistance, we transfected the sensitive MM.1 cells with NALP-7 siRNA which effectively knocked down NALP7 mRNA level by over 80%. The knock-down of NALP-7, however, did not appear to affect the GC sensitivity of the transfected myeloma cells as dexamethasone (dex) treatment effectively caused growth arrest and apoptosis in transfected cells as in the control cells. We have also tested whether suppressing NALP11 expression would overcome the resistance to GC treatment by transfecting the GC-resistant MM.1 cells with NALP11 siRNA. While NALP11 expression was effectively knocked down to less than 20%, the transfected cells remain resistant to GC treatment as in the control cells, suggesting that NALP11 expression is not required to maintain the GC-resistant phenotype. We further investigated the upstream signaling cascades influencing NALP7 and NALP11 expression. Interestingly, dex treatment suppressed the expression of both NALP7 and NALP11 genes in the GC-sensitive MM.1 cells in a time- and dose-dependent manner. Co-treatment with glucocorticoid receptor (GR) antagonist RU486 blocked the down-regulation of NALP7 and NALP11 by dex, suggesting that a functional GR is required to mediate this action. In GC-resistant MM.1 cells which have much reduced levels of wild type GR, NALP7 and NALP11 mRNA levels were not affected by dex treatment, suggesting further that the suppression of NALP7 by GC requires sufficient levels of GR. Our studies demonstrated that the differential expression of two NALP family genes, NALP7 and NALP11, correlates with GC sensitivity in myeloma, and that both genes are regulated by glucocorticoid signaling. The biological significance of their differential regulation in myeloma remains to be determined.

scholarly journals Cryopreservation Preserves Cell-Type Composition and Gene Expression Profiles in Bone Marrow Aspirates From Multiple Myeloma Patients

2021 ◽  
Vol 12 ◽  
Author(s):  
Duojiao Chen ◽  
Mohammad I. Abu Zaid ◽  
Jill L. Reiter ◽  
Magdalena Czader ◽  
Lin Wang ◽  
...  
Keyword(s):  
Gene Expression ◽  
Multiple Myeloma ◽  
Bone Marrow ◽  
Single Cell ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Cell Type ◽  
Myeloma Cells ◽  
Freeze Thaw ◽  
Single Cell Rna Sequencing

Single-cell RNA sequencing reveals gene expression differences between individual cells and also identifies different cell populations that are present in the bulk starting material. To obtain an accurate assessment of patient samples, single-cell suspensions need to be generated as soon as possible once the tissue or sample has been collected. However, this requirement poses logistical challenges for experimental designs involving multiple samples from the same subject since these samples would ideally be processed at the same time to minimize technical variation in data analysis. Although cryopreservation has been shown to largely preserve the transcriptome, it is unclear whether the freeze-thaw process might alter gene expression profiles in a cell-type specific manner or whether changes in cell-type proportions might also occur. To address these questions in the context of multiple myeloma clinical studies, we performed single-cell RNA sequencing (scRNA-seq) to compare fresh and frozen cells isolated from bone marrow aspirates of six multiple myeloma patients, analyzing both myeloma cells (CD138+) and cells constituting the microenvironment (CD138−). We found that cryopreservation using 90% fetal calf serum and 10% dimethyl sulfoxide resulted in highly consistent gene expression profiles when comparing fresh and frozen samples from the same patient for both CD138+ myeloma cells (R ≥ 0.96) and for CD138– cells (R ≥ 0.9). We also demonstrate that CD138– cell-type proportions showed minimal alterations, which were mainly related to small differences in immune cell subtype sensitivity to the freeze-thaw procedures. Therefore, when processing fresh multiple myeloma samples is not feasible, cryopreservation is a useful option in single-cell profiling studies.

scholarly journals Stromal Cells Serve Drug Resistance for Multiple Myeloma via Mitochondrial Transfer: A Study on Primary Myeloma and Stromal Cells

Cancers ◽  
2021 ◽  
Vol 13 (14) ◽  
pp. 3461
Author(s):  
Zsolt Matula ◽  
Gábor Mikala ◽  
Szilvia Lukácsi ◽  
János Matkó ◽  
Tamás Kovács ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Drug Resistance ◽  
Stromal Cells ◽  
Autologous Bone Marrow ◽  
Chemotherapeutic Agents ◽  
Cancer Drug ◽  
Chemotherapeutic Drugs ◽  
Tunneling Nanotubes ◽  
Myeloma Cells ◽  
Mitochondrial Transfer

Recently, it has become evident that mitochondrial transfer (MT) plays a crucial role in the acquisition of cancer drug resistance in many hematologic malignancies; however, for multiple myeloma, there is a need to generate novel data to better understand this mechanism. Here, we show that primary myeloma cells (MMs) respond to an increasing concentration of chemotherapeutic drugs with an increase in the acquisition of mitochondria from autologous bone marrow stromal cells (BM-MSCs), whereupon survival and adenosine triphosphate levels of MMs increase, while the mitochondrial superoxide levels decrease in MMs. These changes are proportional to the amount of incorporated BM-MSC-derived mitochondria and to the concentration of the used drug, but seem independent from the type and mechanism of action of chemotherapeutics. In parallel, BM-MSCs also incorporate an increasing amount of MM cell-derived mitochondria accompanied by an elevation of superoxide levels. Using the therapeutic antibodies Daratumumab, Isatuximab, or Elotuzumab, no similar effect was observed regarding the MT. Our research shows that MT occurs via tunneling nanotubes and partial cell fusion with extreme increases under the influence of chemotherapeutic drugs, but its inhibition is limited. However, the supportive effect of stromal cells can be effectively avoided by influencing the metabolism of myeloma cells with the concomitant use of chemotherapeutic agents and an inhibitor of oxidative phosphorylation.

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