scholarly journals Anti-Bcma PBD MEDI2228 Combats Drug Resistance and Synergizes with Bortezomib and Inhibitors to DNA Damage Response in Multiple Myeloma

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1817-1817 ◽  
Author(s):  
Lijie Xing ◽  
Liang Lin ◽  
Tengteng Yu ◽  
Yuyin Li ◽  
Kenneth Wen ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Dna Damage ◽  
Drug Resistance ◽  
Molecular Mechanisms ◽  
Checkpoint Inhibitors ◽  
Single Agent ◽  
Optimal Dose ◽  
Antibody Drug Conjugate ◽  
Dna Damage And Repair

A novel anti-BCMA antibody drug conjugate (ADC) MEDI2228 preferentially binds to membrane-bound vs soluble BCMA (sBCMA) to effectively deliver the pyrrolobenzodiazepine (PBD) payload tesirine to multiple myeloma (MM) cells (Leukemia. 2019;33: 766). In preclinical models, this ADC targets both MM cells in bulk and CD19+CD138- patient MM progenitor cells. We here study the potency of MEDI2228 in MM cells in the bone marrow (BM) microenvironment and examine molecular mechanisms whereby MEDI2228 overcomes drug resistance. First, MEDI2228, more effectively than its microtubule-binding monomethyl auristatin-F (MMAF) ADC homolog, inhibits proliferation (>1-2-log) and survival of all MM cell lines and MM cells from patients with multiple relapsed and refractory diseases, regardless of BCMA levels, p53 status, and the protection conferred by BM stromal cells and IL-6. Significantly, MM cells with lower BCMA expression and resistance to bortezomib or immunomodulatory drugs (IMiDs, i.e., lenalidomide, pomalidomide) are more susceptible to MEDI2228 vs its MMAF ADC homolog. MEDI2228, but not its MMAF ADC homolog, activates critical DNA damage responses (DDR) via phosphorylation of ATM/ATR kinases, checkpoint kinases (CHK)1/2, and H2AX, associated with induction of multiple DDR pathway-associated genes. Low doses of MEDI2228 and bortezomib (btz) synergistically induce apoptosis of drug-sensitive and -resistant MM cells, at least in part, through modulation of RAD51, a DNA damage and repair protein. Importantly, MEDI2228 further triggers the ATM/ATR-CHK1/2 signaling cascade, associated with increased gH2AX, p21, and apoptosis molecules in MM1S-xenografted tumors in mice. In vivo, a single sub-optimal dose of 0.4 mg/kg MEDI2228 induces superior anti-MM activity than btz, indicating that MEDI2228 is significantly more effective and selective than btz as single agent therapy in vivo. Furthermore, combined treatments with MEDI2228 and btz result in potent tumor depletion and significantly prolonged host survival via increased nuclear gH2AX-expressing microfoci, DNA damage-induced growth arrest and cell death. Significant tumor necrosis is observed earlier in mice receiving both drugs than either agent alone. At 177d, 15% mice in the combination treatment group remain alive and without any tumor. Importantly, no weight loss is noted in all groups, indicating a favorable safety profile of MEDI2228, alone or with btz, in vivo. Moreover, DDR checkpoint inhibitors, i.e., AZD0156 (ATMi), AZD6738 (ATRi), AZD1775 (WEE1i), synergize with MEDI2228 to enhance MM cell cytotoxicity (combination index < 1). This study therefore further supports clinical development of MEDI2228 (NCT03489525) as an important next-generation immunotherapy to improve outcome of MM patients. Disclosures Kinneer: AstraZeneca: Employment. Munshi:Amgen: Consultancy; Abbvie: Consultancy; Oncopep: Consultancy; Takeda: Consultancy; Janssen: Consultancy; Adaptive: Consultancy; Celgene: Consultancy. Anderson:Celgene: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Takeda: Consultancy, Speakers Bureau; Bristol-Myers Squibb: Other: Scientific Founder; Oncopep: Other: Scientific Founder; Sanofi-Aventis: Other: Advisory Board.

Deacetylation Induced Nuclear Condensation of HP1γ Promotes Multiple Myeloma Drug Resistance

2021 ◽  
Author(s):  
Zhiqiang Liu ◽  
Xin Li ◽  
Sheng Wang ◽  
Ying Xie ◽  
Hongmei Jiang ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Dna Damage ◽  
Drug Resistance ◽  
Heterochromatin Protein 1 ◽  
Nuclear Condensation ◽  
Repair Capacity ◽  
Acquired Drug Resistance ◽  
Histone Deacetylase 1

Abstract Acquired chemoresistance to proteasome inhibitors (PIs) is a major obstacle that results in failure to manage patients with multiple myeloma (MM) in the clinic; however, the key regulators and underlying mechanisms are still unclear. In this study, we found that high levels of a chromosomal modifier, heterochromatin protein 1 gamma (HP1γ), are accompanied by a low acetylation level in bortezomib-resistant (BR) MM cells, and aberrant DNA repair capacity is correlated with HP1γ overexpression. Mechanistically, the deacetylation of HP1γ at lysine 5 by histone deacetylase 1 (HDAC1) alleviates HP1γ ubiquitination, and the stabilized HP1γ recruits the mediator of DNA damage checkpoint 1 (MDC1) to induce DNA damage repair. Simultaneously, deacetylation modification and MDC1 recruitment enhance the nuclear condensate of HP1γ, which facilitates the chromatin accessibility of genes governing sensitivity to PIs, such as FOS, JUN and CD40. Thus, targeting HP1γ stability using the HDAC1/2 inhibitor, romidepsin, sensitizes PIs treatment and overcomes drug resistance both in vitro and in vivo. Our findings elucidate a previously unrecognized role of HP1γ in the acquired drug resistance of MM and suggest that targeting HP1γ may be efficacious for overcoming drug resistance in MM patients.

scholarly journals 260 CD47 antibody, AO-176 demonstrates potent anti-tumor activity in pre-clinical solid tumor xenografts as a single agent and in combination with multiple classes of therapeutics

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A282-A282
Author(s):  
Gabriela Andrejeva ◽  
Benjamin Capoccia ◽  
Rachel Delston ◽  
Michael Donio ◽  
Ronald Hiebsch ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
T Cell ◽  
Solid Tumors ◽  
Solid Tumor ◽  
Checkpoint Inhibitors ◽  
Single Agent ◽  
In Vivo Efficacy ◽  
Acidic Conditions ◽  
Anti Tumor Activity

BackgroundCD47 is a cell surface protein expressed on tumors that binds SIRPα on macrophages and dendritic cells resulting in a ”don’t eat me” signal that allows tumors to evade phagocytosis. The highly differentiated monoclonal antibody, AO-176 directly targets CD47 and blocks this signal. AO-176 is currently being tested in phase 1 clinical trials in solid tumors and multiple myeloma. The purpose of this study was to assess in vivo efficacy of AO-176 in solid tumor models as a single agent and in combination with multiple classes of therapeutics including chemotherapeutics, monoclonal antibodies and T-cell checkpoint inhibitors.MethodsCD47 expression levels on solid tumor types were assessed by immunohistochemistry using a tumor tissue microarray. Cell-based binding was performed using flow cytometry under acidic and physiologic pH conditions to characterize the functional activity of AO-176 in the two pH environments representing tumor and normal physiologic environments. In vivo studies were performed using models of solid cancers.ResultsAll 12 solid tumor indications assessed were positive for cell membrane localized CD47 (3.3–98.6 H-scores). Cell-based binding of AO-176 to solid cancer cell lines was significantly greater (1.6–25-fold decrease in EC50, 11–39% increase in Bmax) in acidic conditions as compared to a neutral pH environment, demonstrating improved binding in the lower pH environments associated with solid tumors. AO-176 treatment in solid tumor xenograft models resulted in potent anti-tumor activity as a monotherapy (40–58% TGI) and in combination with paclitaxel in an ovarian model (99% TGI), cisplatin in an ovarian model (84% TGI), cisplatin in a gastric model (76% TGI), and an anti-VEGFR-2 in a gastric model (86% TGI). In vivo efficacy of CD47 blockade alone (~33% TGI) and in combination with anti-PD-1 (74% TGI) and anti-PD-L1 (80% TGI) T-cell checkpoint inhibitors was observed in a syngeneic model of colon cancer using a surrogate anti-CD47 blocking antibody.ConclusionsAO-176 is a differentiated anti-CD47 agent that in addition to blocking the don’t eat me signal, directly kills cancer cells, shows lower binding to normal cells such as RBCs and demonstrates increased binding activity in acidic conditions as found in the microenvironment of solid tumors. AO-176 also elicits potent anti-tumor activity in xenograft and syngeneic models as a single agent and in combination with chemotherapies, monoclonal antibodies and T-cell checkpoint inhibitors. AO-176 is currently in clinical trials as a single agent and in combination in patients with select solid cancers (NCT03834948) and in multiple myeloma (NCT04445701).

scholarly journals Novel Combination Therapy Targeting rDNA Transcription and Histone Deacetylation Provides Effective Treatment for Multiple Myeloma, and Synergises in Bortezomib-Resistant MM

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1945-1945
Author(s):  
Kylee H Maclachlan ◽  
Andrew Cuddihy ◽  
Nadine Hein ◽  
Carleen Cullinane ◽  
Simon J. Harrison ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Multiple Myeloma ◽  
Drug Resistance ◽  
Cell Lines ◽  
Cellular Response ◽  
Single Agent ◽  
Resistant Cell ◽  
Rdna Transcription

Abstract Background: Multiple myeloma (MM) requires combination drug therapies to delay acquired drug resistance and clinical relapse. We co-developed CX-5461, a highly-selective inhibitor of RNA polymerase I-mediated rDNA transcription(1), currently in phase I trials for relapsed haematological malignancies (Peter Mac). CX-5461 produces a targeted nucleolar DNA damage response (DDR), triggering both a p53-dependent and -independent nucleolar stress response and killing malignant cells while sparing normal cells(2,3). Single-agent CX-5461 provides an impressive survival benefit in mouse models of B-cell lymphoma, acute myeloid leukaemia and now MM(2,4,5). However, drug resistance eventually occurs, confirming the need for combination therapies. Aim: To test the efficacy of CX-5461 in combination with the histone deacetylase inhibitor panobinostat, (prioritised from a boutique high-throughput screen of anti-myeloma agents), with a focus on the setting of resistance to proteasome-inhibitors (PIs). Methods: We assessed the impact of CX-5461 and panobinostat on overall survival in mouse models of MM, then surveyed the effects on cellular response and molecular markers of DDR. We developed bortezomib-resistant cell lines and an in vivo model of bortezomib-resistance to test this combination in the setting of PI-resistance. Results: CX-5461 in combination with panobinostat provides a significant survival advantage in both the transplanted Vk*MYC and the 5T33/KaLwRij models, with minimal bone marrow toxicity. The combination showed increased anti-proliferative effects and cell death in vitro. Interestingly, experiments interrogating the downstream cellular response of this combination suggest that the mechanism(s) driving synergy are complex and cell context-dependent. Cell cycle analysis indicates that both CX-5461- and panobinostat-driven cell cycle effects, i.e. G2/M and G1/S arrest, respectively, are dominant in the combination setting in a cell line-dependent manner, suggesting that context-dependent factors such as p53 may influence the cellular response. Mechanistically, in both p53-wild type and -null cell lines we observe an increase in DDR signalling with single agent CX-5461, with only moderate further increase with the combination. Moreover, CX-5461-mediated MYC downregulation is not universally observed, with the combination promoting further downregulation only in some cell lines. Given the potential for affecting global transcription programs downstream of panobinostat, we are performing transcriptome analyses in the combination setting compared to single agent treatment. We have generated bortezomib-resistant cell lines, sequentially increasing drug exposure to establish populations growing at concentrations above the IC90 of the parental lines. The resistant 5T33 cells retain their resistance to bortezomib in vivo and we have demonstrated that CX-5461 remains effective in this model, significantly increasing survival. We are currently examining the combination of CX-5461 with panobinostat in this model of bortezomib-resistance, which will give critical information guiding patient selection for future clinical trials. Conclusion: The rDNA transcription inhibitor CX-5461 synergises in vitro and in vivo with panobinostat, and CX-5461 retains efficacy in the setting of bortezomib-resistant myeloma. References Drygin et al., Cancer Research 2011 Bywater et al., Cancer Cell 2012 Quin et al, Oncotarget, 2016 Devlin et al., Cancer Discovery 2016 Hein et al., Blood 2017 Disclosures Harrison: Janssen-Cilag: Other: Scientific advisory board.

scholarly journals PARP1-Mediated Alt-NHEJ Repair Is a Therapeutic Target in Multiple Myeloma

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3107-3107
Author(s):  
Daniele Caracciolo ◽  
Giada Juli ◽  
Francesca Scionti ◽  
Gaetanina Golino ◽  
Mariamena Arbitrio ◽  
...  
Keyword(s):  
Gene Expression ◽  
Multiple Myeloma ◽  
Dna Damage ◽  
Drug Resistance ◽  
Cell Lines ◽  
Dna Damage Response ◽  
Parp Inhibitor ◽  
Damage Response ◽  
Nhej Repair

Background- Multiple Myeloma (MM) is a hematologic malignancy strongly characterized by genomic instability, which promotes disease progression and drug resistance. We previously demonstrated that LIG3-dependent Alt-NHEJ repair is involved in genomic instability, drug resistance and survival of MM cells. On these premises, we investigated PARP1 as driver component of Alt-NHEJ pathway and new therapeutic target in MM. Materials and methods- Cell proliferation and apoptosis were evaluated with CellTiter-Glo assay and Annexin V staining. Alt-NHEJ repair was evaluated using EJ2-GFP. PARP1, Caspase 3, MYC and DNA Damage Response protein levels were analyzed by Western blot of whole protein extracts. In vivo anti-MM activity was evaluated in NOD-SCID mice bearing subcutaneous H929 and AMO-1 Bortezomib resistant (ABZB) xenografts, daily treated with Olaparib (Selleckchem) via oral gavage. Results - By interrogating public available datasets, we found significant correlation between higher mRNA expression of PARP1 and shorter survival of MM patients. On these findings, we investigated the effect of available PARP inhibitors (PARPi) on MM cell survival. We found that Olaparib, a clinically available PARPi induced a significant reduction of proliferation and clonogenic growth of MM cell lines at low micromolar concentrations. Importantly, Olaparib impaired viability of MM cell lines or primary malignant plasmacells co-cultured with stromal cells, thus overcoming the bone marrow microenvironment supportive effect for MM survival. As result of PARP-mediated Alt-NHEJ repair inhibition, anti-proliferative effects were associated to increase of DNA double-strand breaks (DSBs), activation of DNA damage response, cell cycle arrest and finally apoptosis. To identify predictive biomarkers for PARPi in MM, a published sensitivity gene expression signature was applied to our MM gene expression profiling (GEP) data. Interestingly, this signature was particularly enriched in TC2 MM and secondary plasma cell leukemia (PCL). Therefore, in order to evaluate concordantly modulated sets of genes that were possibly associated to PARPi signature in MM, PARPi-positive and PARPi-negative MM-TC2 cases were compared by GSEA analysis. Interestingly, groups of genes regulated by MYC or involved in DNA repair resulted among the most significantly up-regulated in PARPi-positive versus PARPi-negative MM-TC2 cases. Accordingly, MYC transcript reached the highest median expression levels in sPCL and HMCLs across PC dyscrasia groups, and in MM-TC2 class. Consistently U266 cells, which was quiet insensitive to PARP knockdown or PARP inhibitor Olaparib, were null for c-MYC as compared to multiple myeloma cell lines evaluated in this study. Conversely, as formal proof of our hypothesis, over-expression of c-MYC in U266 cells (MYC-OE) induced cell death upon PARP silencing or PARP inhibitor treatment. Notably, we found that c-MYC-PARP1 loop was also hyper-activated in Bortezomib resistant cells, thus confirming pivotal role of Alt-NHEJ repair in drug resistance development. Remarkably, to demonstrate the in vivo relevance of our findings, we showed that clinically available Parp-inhibitor Olaparib exerted a significant anti-MM activity on both Bortezomib sensitive (H929) and resistant (ABZB) MM cells injected in immunocompromised mice. Conclusion Taken together, our findings indicate that MM cells are dependent on PARP-mediated Alt-NHEJ repair pathway, which therefore represents a novel druggable target pathway in MYC-driven MM cells. Disclosures No relevant conflicts of interest to declare.

scholarly journals Pharmacodynamic, pharmacokinetic, and phase 1a study of bisthianostat, a novel histone deacetylase inhibitor, for the treatment of relapsed or refractory multiple myeloma

2021 ◽  
Author(s):  
Yu-bo Zhou ◽  
Yang-ming Zhang ◽  
Hong-hui Huang ◽  
Li-jing Shen ◽  
Xiao-feng Han ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Drug Targets ◽  
Single Agent ◽  
Hdac Inhibitors ◽  
Preclinical Study ◽  
Parp Cleavage ◽  
Rpmi 8226 ◽  
Ongoing Phase

AbstractHDAC inhibitors (HDACis) have been intensively studied for their roles and potential as drug targets in T-cell lymphomas and other hematologic malignancies. Bisthianostat is a novel bisthiazole-based pan-HDACi evolved from natural HDACi largazole. Here, we report the preclinical study of bisthianostat alone and in combination with bortezomib in the treatment of multiple myeloma (MM), as well as preliminary first-in-human findings from an ongoing phase 1a study. Bisthianostat dose dependently induced acetylation of tubulin and H3 and increased PARP cleavage and apoptosis in RPMI-8226 cells. In RPMI-8226 and MM.1S cell xenograft mouse models, oral administration of bisthianostat (50, 75, 100 mg·kg-1·d-1, bid) for 18 days dose dependently inhibited tumor growth. Furthermore, bisthianostat in combination with bortezomib displayed synergistic antitumor effect against RPMI-8226 and MM.1S cell in vitro and in vivo. Preclinical pharmacokinetic study showed bisthianostat was quickly absorbed with moderate oral bioavailability (F% = 16.9%–35.5%). Bisthianostat tended to distribute in blood with Vss value of 0.31 L/kg. This distribution parameter might be beneficial to treat hematologic neoplasms such as MM with few side effects. In an ongoing phase 1a study, bisthianostat treatment was well tolerated and no grade 3/4 nonhematological adverse events (AEs) had occurred together with good pharmacokinetics profiles in eight patients with relapsed or refractory MM (R/R MM). The overall single-agent efficacy was modest, stable disease (SD) was identified in four (50%) patients at the end of first dosing cycle (day 28). These preliminary in-patient results suggest that bisthianostat is a promising HDACi drug with a comparable safety window in R/R MM, supporting for its further phase 1b clinical trial in combination with traditional MM therapies.

scholarly journals Targeting NSD2-mediated SRC-3 liquid–liquid phase separation sensitizes bortezomib treatment in multiple myeloma

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Jing Liu ◽  
Ying Xie ◽  
Jing Guo ◽  
Xin Li ◽  
Jingjing Wang ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Drug Resistance ◽  
Phase Separation ◽  
Liquid Phase ◽  
Liquid Phase Separation ◽  
Acquired Drug Resistance ◽  
Bortezomib Treatment ◽  
Liquid Liquid Phase Separation

AbstractDevelopment of chemoresistance is the main reason for failure of clinical management of multiple myeloma (MM), but the genetic and epigenetic aberrations that interact to confer such chemoresistance remains unknown. In the present study, we find that high steroid receptor coactivator-3 (SRC-3) expression is correlated with relapse/refractory and poor outcomes in MM patients treated with bortezomib (BTZ)-based regimens. Furthermore, in immortalized cell lines, high SRC-3 enhances resistance to proteasome inhibitor (PI)-induced apoptosis. Overexpressed histone methyltransferase NSD2 in patients bearing a t(4;14) translocation or in BTZ-resistant MM cells coordinates elevated SRC-3 by enhancing its liquid–liquid phase separation to supranormally modify histone H3 lysine 36 dimethylation (H3K36me2) modifications on promoters of anti-apoptotic genes. Targeting SRC-3 or interference of its interactions with NSD2 using a newly developed inhibitor, SI-2, sensitizes BTZ treatment and overcomes drug resistance both in vitro and in vivo. Taken together, our findings elucidate a previously unrecognized orchestration of SRC-3 and NSD2 in acquired drug resistance of MM and suggest that SI-2 may be efficacious for overcoming drug resistance in MM patients.

scholarly journals Vimentin provides the mechanical resilience required for amoeboid migration and protection of the nucleus

2019 ◽  
Author(s):  
Luiza Da Cunha Stankevicins ◽  
Marta Urbanska ◽  
Daniel AD. Flormann ◽  
Emmanuel Terriac ◽  
Zahra Mostajeran ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dendritic Cells ◽  
Cell Migration ◽  
Molecular Mechanisms ◽  
Cell Cortex ◽  
Dna Double Strand Breaks ◽  
Nuclear Positioning ◽  
Mechanical Stiffness

AbstractDendritic cells use amoeboid migration through constricted passages to reach the lymph nodes, and this homing function is crucial for immune responses. Amoeboid migration requires mechanical resilience, however, the underlying molecular mechanisms for this type of migration remain unknown. Because vimentin intermediate filaments (IFs) and microfilaments regulate adhesion-dependent migration in a bidirectional manner, we analyzed if they exert a similar control on amoeboid migration. Vimentin was required for cellular resilience, via a joint interaction between vimentin IFs and F-actin. Reduced actin mobility in the cell cortex of vimentin-reduced cells indicated that vimentin promotes Factin subunit exchange and dynamics. These mechano-dynamic alterations in vimentin-deficient dendritic cells impaired amoeboid migration in confined environments in vitro and blocked lymph node homing in mouse experiments in vivo. Correct nuclear positioning is important in confined amoeboid migration both to minimize resistance and to avoid DNA damage. Vimentin-deficiency also led to DNA double strand breaks in the compressed dendritic cells, pointing to a role of vimentin in nuclear positioning. Together, these observations show that vimentin IF-microfilament interactions provide both the specific mechano-dynamics required for dendritic cell migration and the protection the genome needs in compressed spaces.Summary statementVimentin — in joint action with actin — mediates the mechanical stiffness of cells required for amoeboid cell migration through confined spaces and protects the nucleus from DNA damage.

scholarly journals PIWIL1 Drives Chemoresistance in Multiple Myeloma by Modulating Mitophagy and the Myeloma Stem Cell Population

2022 ◽  
Vol 11 ◽  
Author(s):  
Yajun Wang ◽  
Lan Yao ◽  
Yao Teng ◽  
Hua Yin ◽  
Qiuling Wu
Keyword(s):  
Multiple Myeloma ◽  
Drug Resistance ◽  
Stem Cell ◽  
Cell Population ◽  
Side Population ◽  
Chemotherapeutic Agents ◽  
Stem Cell Population ◽  
Exact Function

As an important member of the Argonaute protein family, PIWI-like protein 1 (PIWIL1) plays a key role in tumor cell viability. However, the exact function of PIWIL1 in multiple myeloma (MM) and the underlying mechanism remain unclear. Here, we revealed that PIWIL1 was highly expressed in myeloma cell lines and newly diagnosed MM patients, and that its expression was notably higher in refractory/relapsed MM patients. PIWIL1 promoted the proliferation of MM cells and conferred resistance to chemotherapeutic agents both in vitro and in vivo. More importantly, PIWIL1 enhanced the formation of autophagosomes, especially mitophagosomes, by disrupting mitochondrial calcium signaling and modulating mitophagy-related canonical PINK1/Parkin pathway protein components. Mitophagy/autophagy inhibitors overcome PIWIL1-induced chemoresistance. In addition, PIWIL1 overexpression increased the proportion of side population (SP) cells and upregulated the expression of the stem cell-associated genes Nanog, OCT4, and SOX2, while its inhibition resulted in opposite effects. Taken together, our findings demonstrated that PIWIL1 induced drug resistance by activating mitophagy and regulating the MM stem cell population. PIWIL1 depletion significantly overcame drug resistance and could be used as a novel therapeutic target for reversing resistance in MM patients.

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