miR‐218 contributes to drug resistance in multiple myeloma via targeting LRRC28

2021 ◽  
Vol 122 (3-4) ◽  
pp. 305-314
Author(s):  
Haifei Chen ◽  
Weiling Cao ◽  
Jiao Chen ◽  
Danbo Liu ◽  
Lingyun Zhou ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Drug Resistance

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 SMAD1 as a biomarker and potential therapeutic target in drug-resistant multiple myeloma

2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Jian Wu ◽  
Min Zhang ◽  
Omar Faruq ◽  
Eldad Zacksenhaus ◽  
Wenming Chen ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Drug Resistance ◽  
Therapeutic Target ◽  
Biological Activities ◽  
Xenograft Model ◽  
Myeloma Cell ◽  
Soft Agar ◽  
Drug Resistant ◽  
Migration Assay

Abstract Background SMAD1, a central mediator in TGF-β signaling, is involved in a broad range of biological activities including cell growth, apoptosis, development and immune response, and is implicated in diverse type of malignancies. Whether SMAD1 plays an important role in multiple myeloma (MM) pathogenesis and can serve as a therapeutic target are largely unknown. Methods Myeloma cell lines and primary MM samples were used. Cell culture, cytotoxicity and apoptosis assay, siRNA transfection, Western blot, RT-PCR, Soft-agar colony formation, and migration assay, Chromatin immunoprecipitation (Chip), animal xenograft model studies and statistical analysis were applied in this study. Results We demonstrate that SMAD1 is highly expressed in myeloma cells of MM patients with advanced stages or relapsed disease, and is associated with significantly shorter progression-free and overall survivals. Mechanistically, we show that SMAD1 is required for TGFβ-mediated proliferation in MM via an ID1/p21/p27 pathway. TGF-β also enhanced TNFα-Induced protein 8 (TNFAIP8) expression and inhibited apoptosis through SMAD1-mediated induction of NF-κB1. Accordingly, depletion of SMAD1 led to downregulation of NF-κB1 and TNFAIP8, resulting in caspase-8-induced apoptosis. In turn, inhibition of NF-κB1 suppressed SMAD1 and ID1 expression uncovering an autoregulatory loop. Dorsomorphin (DM), a SMAD1 inhibitor, exerted a dose-dependent cytotoxic effect on drug-resistant MM cells with minimal cytotoxicity to normal hematopoietic cells, and further synergized with the proteasomal-inhibitor bortezomib to effectively kill drug-resistant MM cells in vitro and in a myeloma xenograft model. Conclusions This study identifies SMAD1 regulation of NF-κB1/TNFAIP8 and ID1-p21/p27 as critical axes of MM drug resistance and provides a potentially new therapeutic strategy to treat drug resistance MM through targeted inhibition of SMAD1.

FTY720 Induces Apoptosis in Multiple Myeloma Cells and Overcomes Drug Resistance

2005 ◽  
Vol 65 (16) ◽  
pp. 7478-7484 ◽  
Author(s):  
Hiroshi Yasui ◽  
Teru Hideshima ◽  
Noopur Raje ◽  
Aldo M. Roccaro ◽  
Norihiko Shiraishi ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Drug Resistance ◽  
Myeloma Cells

scholarly journals Identification and Characterization of Multiple Myeloma Stem Cell-Like Cells

Cancers ◽  
2021 ◽  
Vol 13 (14) ◽  
pp. 3523
Author(s):  
Wancheng Guo ◽  
Haiqin Wang ◽  
Peng Chen ◽  
Xiaokai Shen ◽  
Boxin Zhang ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Drug Resistance ◽  
Stem Cell ◽  
New Drugs ◽  
Cell Therapies ◽  
High Relapse Rate ◽  
High Incidence ◽  
Poorly Differentiated ◽  
Identification And Characterization

Multiple myeloma (MM) is a B-cell tumor of the blood system with high incidence and poor prognosis. With a further understanding of the pathogenesis of MM and the bone marrow microenvironment, a variety of adjuvant cell therapies and new drugs have been developed. However, the drug resistance and high relapse rate of MM have not been fundamentally resolved. Studies have shown that, in patients with MM, there is a type of poorly differentiated progenitor cell (MM stem cell-like cells, MMSCs). Although there is no recognized standard for identification and classification, it is confirmed that they are closely related to the drug resistance and relapse of MM. This article therefore systematically summarizes the latest developments in MMSCs with possible markers of MMSCs, introduces the mechanism of how MMSCs work in MM resistance and recurrence, and discusses the active pathways that related to stemness of MM.

β-lapachone, a novel plant product, overcomes drug resistance in human multiple myeloma cells

2002 ◽  
Vol 30 (7) ◽  
pp. 711-720 ◽  
Author(s):  
Deepak Gupta ◽  
Klaus Podar ◽  
Yu-Tzu Tai ◽  
Boris Lin ◽  
Teru Hideshima ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Drug Resistance ◽  
Myeloma Cells ◽  
Plant Product ◽  
Human Multiple Myeloma

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.

scholarly journals Re-Constructing and Exploiting Transcriptional Regulatory Networks in Multiple Myeloma Drug Resistance

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5544-5544
Author(s):  
Rafael Renatino-Canevarolo ◽  
Praneeth Reddy Sudalagunta ◽  
Maria D Coelho Siqueira Silva ◽  
Mark B. Meads ◽  
Alexandre Tungesvik ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Drug Resistance ◽  
Board Of Directors ◽  
Ex Vivo ◽  
Low Frequency ◽  
Gene Clusters ◽  
Patient Specific ◽  
Advisory Committees ◽  
Regulatory Circuits ◽  
Transcriptional Regulatory

Problem: Multiple myeloma (MM) is a treatable yet incurable hematologic cancer that lacks predictive biomarkers. Approach: Here we apply a systems biology approach to determine patient-specific mechanisms, as well as signatures of drug resistance in MM. To achieve this goal, we have combined ex vivo drug sensitivity data from 307 MM fresh primary samples tested with 162 drugs and combinations, with paired molecular data (RNAseq and mutational profiling) from a larger overlapping cohort of 606 MM samples from Moffitt's Multiple Myeloma Working Group (MMWG) repository in collaboration with M2Gen/Oncology Research Information Exchange Network (ORIEN). With the purpose of decoupling biological function from intracellular control mechanisms, we have re-constructed a MM-specific transcriptional regulatory network composed of clusters of co-expressing genes. We demonstrate how this gene cluster network regulates biology, and how different biological functions (e.g. Proteasome, Ribosome, Oxidative Phosphorylation) share common regulatory circuits. We have used gene set enrichment analysis (GSEA) to identify gene clusters with transcriptional profiles, and investigated mutations associated with drug resistance. Results: As a preliminary validation of this approach, we have confirmed established mechanisms of resistance (MOR) to targeted therapies, as well as proposed novel MOR to clinically relevant and experimental drugs in MM, as well as putative synergistic drug combinations. In addition, we have identified a list of low frequency mutations (<5%) indirectly involved in drug resistance (or sensitivity) through modulation of expression of gene clusters correlated with drug resistance (GSEA). This would suggest that low frequency mutations in a number of different genes, targeting a shared transcriptional regulatory mechanism, can drive drug resistance in MM, while been overlooked by statistical analysis of each individual gene. We have also explored evolution of drug resistance in sequential samples. Consistent with altered transcriptional programming in therapeutic escape, single sample GSEA demonstrated cumulative dysregulation of cancer-related genes with increasing lines of therapy. We have identified 60 MM-specific transcriptional core auto-regulatory circuits (CRC) correlated with ex vivo drug resistance, suggesting that characterization of transcriptional regulatory circuits is a critical approach to infer mechanisms of MM resistance, and providing a novel rationale for combination therapy. We hypothesized that identifying and targeting these transcriptional CRCs could facilitate patient-specific rational combination therapies, with the goal to overcome therapy resistance in the clinic. As proof-of-principle, we have identified a novel transcriptional network consisting of 3 of these CRCs (FOXP1, JUNB and JUN) associated with BCL2 inhibitor (BCL2i) response in MM. Our preliminary data suggests that this transcriptional regulatory circuit is associated to t(11;14) MM through CCND1 up-regulation, but is also present in non-t(11;14) BCL2i-sensitive primary samples, and can be modulated to induce BCL2i sensitivity in non-t(11;14) MM through HDAC inhibitors. Conclusion and next steps: Preliminary results confirm the potential of this combination of unsupervised and supervised, yet functionally testable approach, to infer novel, and patient-specific MOR for MM drugs. Disclosures Dai: M2Gen: Employment. Dalton:MILLENNIUM PHARMACEUTICALS, INC.: Honoraria. Shain:Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Sanofi Genzyme: Membership on an entity's Board of Directors or advisory committees; AbbVie: Research Funding; Adaptive Biotechnologies: Consultancy; Janssen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees.

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.

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