期刊
CANCERS
卷 12, 期 8, 页码 -出版社
MDPI
DOI: 10.3390/cancers12082206
关键词
multiple myeloma; BUB1; chromosome segregation error; chromosomal instability; clonogenicity
类别
资金
- National Cancer Center Research and Development Funds [26-A-4, 29-A-3]
- Ministry of Health, Labor, and Welfare of Japan [H26-kakushin-teki-gan-ippan-074]
- AMED [JP16ck0106077h003, JP17ck0106348h0001, JP18ck0106348h0002, JP19ck0106348h0003]
- Ministry of Education, Culture, Sports, Science, and Technology of Japan (MEXT KAKENHI) [16K09856, 18K08367]
- Japanese Society for Myeloma Research Award
- Grants-in-Aid for Scientific Research [18K08367, 16K09856] Funding Source: KAKEN
Chromosome instability (CIN), the hallmarks of cancer, reflects ongoing chromosomal changes caused by chromosome segregation errors and results in whole chromosomal or segmental aneuploidy. In multiple myeloma (MM), CIN contributes to the acquisition of tumor heterogeneity, and thereby, to disease progression, drug resistance, and eventual treatment failure; however, the underlying mechanism of CIN in MM remains unclear. Faithful chromosomal segregation is tightly regulated by a series of mitotic checkpoint proteins, such as budding uninhibited by benzimidazoles 1 (BUB1). In this study, we found that BUB1 was overexpressed in patient-derived myeloma cells, and BUB1 expression was significantly higher in patients in an advanced stage compared to those in an early stage. This suggested the involvement of aberrant BUB1 overexpression in disease progression. In human myeloma-derived cell lines (HMCLs), BUB1 knockdown reduced the frequency of chromosome segregation errors in mitotic cells. In line with this, partial knockdown of BUB1 showed reduced variations in chromosome number compared to parent cells in HMCLs. Finally, BUB1 overexpression was found to promote the clonogenic potency of HMCLs. Collectively, these results suggested that enhanced BUB1 expression caused an increase in mitotic segregation errors and the resultant emergence of subclones with altered chromosome numbers and, thus, was involved in CIN in MM.
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