Abstract 972: 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
Authors: Tai Yu-Tzu , Acharya Chirag , Zhong Mike Y. , Cea Michele , Cagnetta Antonia , Richardson Paul , Munshi Nikhil C. , Anderson Kenneth C. 
Published: May 2015

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, consistent with high and restrictive BCMA expression in PCs but not normal tissues by gene expression profiling and immunohistochemistry in previously published reports. 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&lt;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&lt;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 in the BM milieu. BCMA shRNA significantly blocks viability of MM cells (RPMI8226, MM1R, H929) and anti-apoptotic protein MCL-1. Conversely, overexpression of BCMA in multiple MM cell lines (RPMI8226, MM1R, H929) by pCMV6/BCMA vector upregulates MCL-1 expression and MIP-1α, as well as NFκB p65 DNA binding activity. Importantly, stimulation of MM cells by APRIL, a cognate ligand for BCMA and mainly secreted by osteoclasts in the BM milieu, induces NFκB DNA binding activity and activates PI3K/AKT and ERK1/2 signaling. 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 (VEGF, IL-8, CXCL10, RANTES) were also significantly induced upon APRIL stimulation. In contrast, BCMA-Fc protein that blocks APRIL binding to BCMA, inhibits secretion of these cytokines/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 define active APRIL/BCMA signaling cascade 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 # 14-A-4420-AACR) to treat MM patients.

Citation Format: Yu-Tzu Tai, Chirag Acharya, Mike Y. Zhong, Michele Cea, Antonia Cagnetta, Paul Richardson, Nikhil C. Munshi, Kenneth C. Anderson. 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. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 972. doi:10.1158/1538-7445.AM2014-972