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

Molecular Cancer

Artur Jurczyszyn¹  Meral Beksac²  Siegfried Janz³  Anja Seckinger⁴  Dirk Hose⁴  Fenghuang Zhan⁵  Ye Yang⁶  Mengjie Guo⁶  Chunyan Gu⁶  Jingxuan Pan⁷  Wang Wang⁸  Xiaozhu Tang⁸  Yajun Wang⁸  Tingting Xu⁸  Rongfang Wei⁸  Yanxin Zhang⁸ 

[1] Department of Hematology, Jagiellonian University Medical College, Cracow, Poland;Department of Hematology, School of Medicine, Ankara University, Ankara, Turkey;Division of Hematology and Oncology, Medical College of Wisconsin, Milwaukee, USA;Laboratory of Hematology and Immunology & Labor für Myelomforschung, Vrije Universiteit Brussel (VUB), Jette, Belgium;Myeloma Center, University of Arkansas for Medical Sciences, Little Rock, USA;Nanjing Hospital of Chinese Medicine affiliated to Nanjing University of Chinese Medicine, Nanjing, China;School of Medicine & Holistic Integrative Medicine, Nanjing University of Chinese Medicine, 138 Xianlin Road, 210023, Nanjing, China;Nanjing Hospital of Chinese Medicine affiliated to Nanjing University of Chinese Medicine, Nanjing, China;State Key Laboratory of Ophthalmology, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Zhongshan Ophthalmic Center, Sun Yat-sen University, 54 South Xianlie Road, 510060, Guangzhou, China;School of Medicine & Holistic Integrative Medicine, Nanjing University of Chinese Medicine, 138 Xianlin Road, 210023, Nanjing, China;

关键词: Multiple myeloma;    CHEK1;    circCHEK1_246aa;    Proliferation;    Drug resistance;    Chromosomal instability;   

DOI  :  10.1186/s12943-021-01380-0

来源: Springer

【 摘 要 】

BackgroundMultiple 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.MethodsCell 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.ResultsWe 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.ConclusionsOur 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.

【 授权许可】

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