Wang Wang, Wei Rongfang, Liu Shijia, Qiao Li, Hou Jianhao, Gu Chunyan, Yang Ye
School of Medicine and Life Sciences, Nanjing University of Chinese Medicine Nanjing 210023, Jiangsu, China.
The Third Affiliated Hospital of Nanjing University of Chinese Medicine Nanjing 210001, Jiangsu, China.
Am J Transl Res. 2019 Jul 15;11(7):4139-4150. eCollection 2019.
Cellular adhesion-mediated drug resistance (CAM-DR) occurs frequently in patients with relapsed or refractory multiple myeloma (MM). Elucidating the mechanism underlying CAM-DR and developing the corresponding treatment may prove to be promising for the clinical management of MM. Bruton's tyrosine kinase (BTK) has been attracting attention in relation to MM progression and drug resistance. BTK was reported to be associated with cell surface CXCR4, a classic cell adhesion molecule and homing factor. However, the exact association between BTK and CAM-DR in MM remains elusive. In this study, we demonstrated that promoting BTK expression induced MM cell adherence to the extracellular matrix (ECM) and stromal cells in vitro and in vivo, and that CAM-DR could be reversed by separating MM cells from ECM or stromal cells. Enhancing BTK expression levels increased CXCR4 expression in MM cells. In addition, BTK may bind directly with CXCR4 and prevent its ubiquitination-induced degradation. Finally, a BTK inhibitor exerted synergistic therapeutic effects with bortezomib in a 5TMM3VT MM mouse model. These findings revealed a novel role of BTK in CAM-DR and may provide a promising approach to MM treatment.
细胞黏附介导的耐药性（CAM-DR）在复发或难治性多发性骨髓瘤（MM）患者中频繁出现。阐明CAM-DR的潜在机制并开发相应的治疗方法可能对MM的临床管理具有重要意义。布鲁顿酪氨酸激酶（BTK）在MM进展和耐药性方面一直备受关注。据报道，BTK与细胞表面的CXCR4相关，CXCR4是一种经典的细胞黏附分子和归巢因子。然而，BTK与MM中CAM-DR的确切关联仍不清楚。在本研究中，我们证明促进BTK表达可在体外和体内诱导MM细胞黏附于细胞外基质（ECM）和基质细胞，并且通过将MM细胞与ECM或基质细胞分离可逆转CAM-DR。提高BTK表达水平可增加MM细胞中CXCR4的表达。此外，BTK可能直接与CXCR4结合并防止其泛素化诱导的降解。最后，在5TMM3VT MM小鼠模型中，BTK抑制剂与硼替佐米发挥协同治疗作用。这些发现揭示了BTK在CAM-DR中的新作用，并可能为MM治疗提供一种有前景的方法。
