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

• Published in: Molecular cancer Vol. 20; no. 1; p. 84
• Main Authors: Gu, Chunyan, Wang, Wang, Tang, Xiaozhu, Xu, Tingting, Zhang, Yanxin, Guo, Mengjie, Wei, Rongfang, Wang, Yajun, Jurczyszyn, Artur, Janz, Siegfried, Beksac, Meral, Zhan, Fenghuang, Seckinger, Anja, Hose, Dirk, Pan, Jingxuan, Yang, Ye
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 05.06.2021; BioMed Central; BMC
• Subjects: Acid phosphatase (tartrate-resistant); Animals; Antibodies; Biotechnology; Bone and Bones - pathology; Bone growth; Bone lesions; Bone marrow; Cancer; Cell cycle; Cell differentiation; Cell growth; Cell proliferation; Checkpoint Kinase 1 - genetics; CHEK1; Chromosomal instability; Chromosomal Instability - genetics; circCHEK1_246aa; Cloning; DNA sequencing; Drug resistance; Gene expression; Genetic aspects; Genomic instability; Health aspects; Heterografts; Humans; Immunofluorescence; Kinases; Laboratory animals; Mice; mRNA; Multiple myeloma; Multiple Myeloma - genetics; Multiple Myeloma - pathology; Nucleotide sequencing; Osteoclastogenesis; Osteoclasts - metabolism; Osteoclasts - pathology; Patients; Phosphatases; Plasma cells; Plasmids; Proliferation; Proteins; RNA; RNA, Circular - genetics; Scientific equipment and supplies industry; Therapeutic applications; Transfection; Variance analysis; Xenografts; United States; United States > US; China; Germany; Chromosomal instability; Proliferation; Drug resistance; circCHEK1_246aa; CHEK1; Multiple myeloma
• ISSN: 1476-4598; 1476-4598
• DOI: 10.1186/s12943-021-01380-0

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. 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. 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. 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.