Aberrant BUB1 Overexpression Promotes Mitotic Segregation Errors and Chromosomal Instability in Multiple Myeloma
Aberrant BUB1 Overexpression Promotes Mitotic Segregation Errors and Chromosomal Instability in Multiple Myeloma
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DOI：
10.3390/cancers12082206
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发表时间：
2020-08-01
期刊：
影响因子：
5.2
通讯作者：
Kuroda, Junya
中科院分区：
文献类型：
--
作者：
Fujibayashi, Yuto;Isa, Reiko;Kuroda, Junya
染色体不稳定性（CIN）是癌症的标志，反映了由染色体分离错误引起的持续染色体变化，并导致整个染色体或节段非整倍性。在多发性骨髓瘤（MM）中，CIN有助于获得肿瘤异质性，从而导致疾病进展、耐药性和最终治疗失败;然而，MM中CIN的潜在机制仍不清楚。忠实的染色体分离受到一系列有丝分裂检查点蛋白的严格调控，例如不受苯并咪唑1（BUB 1）抑制的出芽。在这项研究中，我们发现BUB 1在患者来源的骨髓瘤细胞中过表达，并且与早期患者相比，晚期患者的BUB 1表达显著更高。这表明异常BUB 1过表达参与疾病进展。在人骨髓瘤细胞系（HMCL）中，BUB 1敲低降低了有丝分裂细胞中染色体分离错误的频率。与此一致，与HMCL中的亲本细胞相比，BUB 1的部分敲除显示染色体数目的变化减少。最后，发现BUB 1过表达促进HMCL的克隆形成效力。总的来说，这些结果表明，增强BUB 1表达引起有丝分裂分离错误的增加，并导致染色体数目改变的亚克隆的出现，因此，参与MM中的CIN。
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.