BTK induces CAM-DR through regulation of CXCR4 degradation in multiple myeloma

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.