BCMA Is Essential for the Survival of Long-lived Bone Marrow Plasma Cells

Abstract

Long-lived humoral immunity is manifested by the ability of bone marrow plasma cells (PCs) to survive for extended periods of time. Recent studies have underscored the importance of BLyS and APRIL as factors that can support the survival of B lineage lymphocytes. We show that BLyS can sustain PC survival in vitro, and this survival can be further enhanced by interleukin 6. Selective up-regulation of Mcl-1 in PCs by BLyS suggests that this ␣ -apoptotic gene product may play an important role in PC survival. Blockade of BLyS, via transmembrane activator and cyclophilin ligand interactor-immunoglobulin treatment, inhibited PC survival in vitro and in vivo. Heightened expression of B cell maturation antigen (BCMA), and lowered expression of transmembrane activator and cyclophilin ligand interactor and BAFF receptor in PCs relative to resting B cells suggests a vital role of BCMA in PC survival. Affirmation of the importance of BCMA in PC survival was provided by studies in BCMA Ϫ / Ϫ mice in which the survival of long-lived bone marrow PCs was impaired compared with wild-type controls. These findings offer new insights into the molecular basis for the long-term survival of PCs.

A novel BCMA/CD3 bispecific T-cell engager for the treatment of multiple myeloma induces selective lysis in vitro and in vivo

“…12 BCMA − / − mice have impaired long-term plasma cell survival but do not show defects in short-term production of immunoglobulins, early humoral immune response and B-cell development. 13,14 BCMA is expressed on MM cell lines and malignant plasma cells with high prevalence and increased expression levels during disease progression from monoclonal gammopathy of undetermined significance (MGUS) to smoldering myeloma to active MM. [15][16][17][18][19][20][21] BCMA is also expressed on plasmacytoid dendritic cells, which promote MM cell growth, survival and drug resistance.…”

“…21 Apart from expression on peripheral and bone marrow resident plasma cells and plasmacytoid dendritic cells, BCMA is not expressed on naive and most memory B cells, CD34+ hematopoietic cells, or any other normal tissue cells. 12,14,17,24 Furthermore, BCMA overexpression or APRIL stimulation via BCMA in MM cells can directly upregulate key immune checkpoint molecules, which may contribute to the immunosuppressive bone marrow microenvironment. 25 In this manuscript, we describe the preclinical profile of a novel BCMA BiTE antibody construct (BI 836909).…”

Immunological memories of the bone marrow

“…It would not be too surprising if adhesion between plasma cells and stromal cells was mediated by redundant receptors. Likewise, as discussed above, BCMA can be activated by either April or BAFF 36. VCAM‐1 and ICAM‐1, the ligands of VLA‐4 and LFA‐1, are expressed by bone marrow stromal cells40 and, expectedly, in the bone marrow most if not all plasma cells contact stromal cells expressing VCAM‐1 41, 42.…”

“…An essential signal is activation of the B‐cell maturation antigen (BCMA/CD269) by one of its ligands, B‐cell activating factor (BAFF/BLyS/CD257), or a proliferation inducing ligand (APRIL/CD256) 36. BCMA is encoded by the tumor necrosis factor receptor superfamily member 17 gene ( TNFRSF17 ), and signaling through the NF‐κB pathway regulates expression of the myeloid leukemia cell differentiation protein MCL1, which is essential for survival of bone marrow plasma cells 37.…”

BAFF/BLyS inhibitors: A new prospect for treatment of systemic lupus erythematosus

“…BCMA 2/2 mice, when compared with controls, have similar serum immunoglobulin levels, normal T-cell independent immune responses to nitrophenyl-Ficoll (NP-Ficoll), and normal serum titres in response to immunisation with a T-cell-dependent antigen, nitrophenyl-chicken gamma globulin (NP-CGG), out to day 45 (16). However, administration of TACI-Ig (blocking both BAFF and APRIL signaling) 6 weeks after an immunization, when the antigen-specific cells should have all been activated and the response effectively resolved, resulted in the number of antigen-specific antibody secreting cells dropping, suggesting that BAFF signaling does play an important role in cell survival of antibody-producing plasma cells in the bone marrow (17). As BCMA is the only receptor for BAFF expressed on long-lived bone marrow plasma cells, treatment with TACI-Ig in that experiment was likely to be acting by blocking BCMA signaling.…”