Epigenetic silencing of miR-137 induces drug resistance and chromosomal instability by targeting AURKA in multiple myeloma

Leukemia ◽  
2016 ◽  
Vol 31 (5) ◽  
pp. 1123-1135 ◽  
Author(s):  
Y Qin ◽  
S Zhang ◽  
S Deng ◽  
G An ◽  
X Qin ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Drug Resistance ◽  
Chromosomal Instability ◽  
Epigenetic Silencing

scholarly journals Chromosomal instability and acquired drug resistance in multiple myeloma

Oncotarget ◽  
2017 ◽  
Vol 8 (44) ◽  
pp. 78234-78244 ◽  
Author(s):  
Wang Wang ◽  
Yi Zhang ◽  
Ruini Chen ◽  
Zhidan Tian ◽  
Yongpin Zhai ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Drug Resistance ◽  
Chromosomal Instability ◽  
Acquired Drug Resistance

scholarly journals CHEK1 and circCHEK1_246aa Promote Multiple Myeloma Malignancy By Evoking Chromosomal Instability and Bone Lesion

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 9-10
Author(s):  
Ye Yang ◽  
Chunyan Gu ◽  
Wang Wang ◽  
Xiaozhu Tang
Keyword(s):  
Multiple Myeloma ◽  
Cell Proliferation ◽  
Drug Resistance ◽  
Chromosomal Instability ◽  
Cellular Proliferation ◽  
Plasma Cells ◽  
Osteoclast Differentiation ◽  
Bone Lesion ◽  
Catalytic Center ◽  
Bm Niche

Key findings CHEK1 and circCHEK1_246aa induce multiple myeloma cell proliferation, drug resistance, and bone lesion formation CHEK1 and circCHEK1_246aa evoke myeloma chromosomal instability, partially through CEP170 activation Abstract Multiple myeloma (MM) is characterized by clonal expansion of plasma cells in the bone marrow (BM). Therefore, effective therapeutic interventions must target both myeloma cells and the BM niche. In the present study, we first demonstrated that CHEK1 expression was significantly increased in human MM samples relative to normal plasma cells, and that in MM patients, high CHEK1 expression was associated with poor outcomes. CHEK1 overexpression increased cellular proliferation in MM cells and evoked drug resistance in vitro, while CHEK1 knockdown abrogated this effect. Moreover, CHEK1 was a high-risk gene for poor outcome in MM patients, and, in paired samples from MM patients taken from newly diagnosed and relapsed MM, CHEK1 expression was upregulated. CHEK1-mediated increases in cell proliferation and drug resistance were due in part to CHEK1-induced chromosomal instability (CIN), as demonstrated by Giemsa staining, exon sequencing, and immunofluorescence. CHEK1 activated CIN, partly by phosphorylating CEP170. Interestingly, CHEK1 promoted osteoclast differentiation by direct phosphorylation and activation of NFATc1, indicating that CHEK1 inhibition could target both MM cell proliferation and macrophage osteoclast differentiation in the BM niche. Intriguingly, we also discovered that MM cells expressed circCHEK1_246aa, a circular CHEK1 RNA, which encoded and was translated to the CHEK1 kinase catalytic center. Transfection of circCHEK1_246aa increased MM CIN and osteoclast differentiation similarly to CHEK1 overexpression, suggesting that MM cells could secrete circCHEK1_246aa in the BM niche to increase the invasive potential of MM cells and promote osteoclast differentiation. Finally, we demonstrated in vivo in xenograft models that CHEK1 overexpression prompted MM proliferation and drug resistance, while CHEK1 knockdown conversely inhibited MM growth. Together, these findings suggest that targeting the enzymatic catalytic center encoded by CHEK1 mRNA and circCHEK1_246aa is a promising therapeutic modality to target both MM cells and the BM niche. Figure Disclosures No relevant conflicts of interest to declare.

scholarly journals CHEK1 and circCHEK1_246aa evoke chromosomal instability and induce bone lesion formation in multiple myeloma

2021 ◽  
Vol 20 (1) ◽  
Author(s):  
Chunyan Gu ◽  
Wang Wang ◽  
Xiaozhu Tang ◽  
Tingting Xu ◽  
Yanxin Zhang ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Cell Proliferation ◽  
Drug Resistance ◽  
Chromosomal Instability ◽  
Plasma Cells ◽  
Osteoclast Differentiation ◽  
Bone Lesion ◽  
Catalytic Center ◽  
Bm Niche

Abstract Background Multiple myeloma (MM) is still incurable and characterized by clonal expansion of plasma cells in the bone marrow (BM). Therefore, effective therapeutic interventions must target both myeloma cells and the BM niche. Methods Cell proliferation, drug resistance, and chromosomal instability (CIN) induced by CHEK1 were confirmed by Giemsa staining, exon sequencing, immunofluorescence and xenograft model in vivo. Bone lesion was evaluated by Tartrate-resistant acid phosphatase (TRAP) staining. The existence of circCHEK1_246aa was evaluated by qPCR, Sanger sequencing and Mass Spectrometer. Results We demonstrated that CHEK1 expression was significantly increased in human MM samples relative to normal plasma cells, and that in MM patients, high CHEK1 expression was associated with poor outcomes. Increased CHEK1 expression induced MM cellular proliferation and evoked drug-resistance in vitro and in vivo. CHEK1-mediated increases in cell proliferation and drug resistance were due in part to CHEK1-induced CIN. CHEK1 activated CIN, partly by phosphorylating CEP170. Interestingly, CHEK1 promoted osteoclast differentiation by upregulating NFATc1 expression. Intriguingly, we discovered that MM cells expressed circCHEK1_246aa, a circular CHEK1 RNA, which encoded and was translated to the CHEK1 kinase catalytic center. Transfection of circCHEK1_246aa increased MM CIN and osteoclast differentiation similarly to CHEK1 overexpression, suggesting that MM cells could secrete circCHEK1_246aa in the BM niche to increase the invasive potential of MM cells and promote osteoclast differentiation. Conclusions Our findings suggest that targeting the enzymatic catalytic center encoded by CHEK1 mRNA and circCHEK1_246aa is a promising therapeutic modality to target both MM cells and BM niche.

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

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 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.

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