Abstract
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.
Highlights
Multiple myeloma (MM) is a cytogenetically and molecularly heterogeneous hematological malignancy that originates from plasma cells and remains mostly incurable, despite recent therapeuticCancers 2020, 12, 2206; doi:10.3390/cancers12082206 www.mdpi.com/journal/cancersCancers 2020, 12, 2206 advances
BUB1 expression was first examined in 10 human myeloma-derived cell lines (HMCLs) and normal plasma cells
Tended to be higher in CD138-positive myeloma cells from monoclonal gammopathy of undetermined significance (MGUS) and newly diagnosed MM (NDMM) compared to normal plasma cells, but the difference was not significant
Summary
Multiple myeloma (MM) is a cytogenetically and molecularly heterogeneous hematological malignancy that originates from plasma cells and remains mostly incurable, despite recent therapeuticCancers 2020, 12, 2206; doi:10.3390/cancers12082206 www.mdpi.com/journal/cancersCancers 2020, 12, 2206 advances. MM provides an excellent model through which understanding of the multistep evolutional process of cancer progression might be achieved. Subsequent to the primary event, numerous types of secondary cytogenetic or molecular aberrations, including chromosomal translocations, copy number abnormalities, somatic mutations, and epigenetic alterations, emerge in an overlapping manner in myeloma cells. This multistep acquisition of a series of genetic abnormalities gives rise to subclones with a selective advantage for disease progression, even under therapeutic pressure [1,2,3,4,5,6]. The mechanisms underlying the acquisition of additional chromosome abnormality remain obscure
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