Constitutive B-Cell Maturation Antigen (BCMA) Activation In Human Multiple Myeloma Cells Promotes Myeloma Cell Growth and Survival In The Bone Marrow Microenvironment Via Upregulated MCL-1 and NFκB Signaling

B cell maturation antigen (BCMA), a member of the tumor necrosis factor receptor superfamily (TNFRSF17), is selectively induced during plasma cell (PC) differentiation and is commonly expressed at high levels in malignant PCs. Using real time RT-PCR, we here first showed that BCMA mRNA was upregulated in CD138+ PCs from MM patients compared to normal healthy donors (p<0.04), consistent with high and restrictive BCMA expression in PCs but not normal tissues by gene expression profiling and immunohistochemistry (IHC) in a recent report (Clin Cancer Res 2013;19:2048-60). As a specific MM antigen, BCMA is universally expressed on the MM cell surface, confirmed by CD38+BCMA+ dual immunofluorescence staining. We next found that plasmacytoid dendritic cells (pDC), which support MM cell growth, survival, and drug resistance in the bone marrow (BM) microenvironment, have detectable BCMA mRNA at significantly (9-50-fold) lower levels than CD138+ plasma PCs (p<0.005 for each paired sample) from either MM patients or normal donors. Interestingly, as seen in CD138+ PCs, BCMA transcript is considerably elevated in pDC from MM patients vs. normal donors (p<0.03). In contrast, BCMA is hardly detectable in CD138-negative cells from BM aspirates of MM patients. We further define molecular mechanisms of BCMA activation in MM cells. Overexpression of BCMA in multiple MM cell lines (RPMI8226. MM1S, MM1R) by BCMA-expression vector significantly upregulates MCL-1 expression and MIP-1a, as well as NFkB p65 DNA binding activity. Conversely, BCMA siRNA blocked NFkB signaling and expression of anti-apoptotic proteins, leading to decreased MM cell viability. Importantly, stimulation of MM cells by APRIL, which is a cognate ligand for BCMA and mainly secreted by osteoclasts in the BM milieu, activated the canonical NFκB and PI3K/AKT pathways. APRIL also induces pro-survival/anti-apoptotic targets (BCL2A1, NFκB1, NFκB2) and chemotactic/osteoclast activating factors (MIP-1α and MIP1β) in a dose-dependent manner. Angiogenesis and adhesion/chemoattractant factors (IL-8, CXCL10, RANTES, MDC/ccl22) were also significantly induced upon APRIL stimulation. Conversely, BCMA-Fc protein inhibited APRIL to bind BCMA and inhibit secretion of APRIL-induced chemokines, indicating specific response of engagement of BCMA by APRIL in BCMA-expressing MM cells. Finally, APRIL induced adhesion and migration of MM cells whereas BCMA-Fc blocked APRIL-induced responses. Together, our results established active APRIL/BCMA signaling in MM in the BM microenvironment, thus providing a niche for MM disease progression. Moreover, these results strongly support rapid bench to bedside translation of the novel antagonistic anti-BCMA antibody drug conjugate (abstract #56099) to treat MM patients with a likely favorable therapeutic window.