Binding of B‐cell maturation antigen to B‐cell activating factor induces survival of multiple myeloma cells by activating Akt and JNK signaling pathways

Abstract

B-cell maturation antigen (BCMA) is expressed on normal and malignant plasma cells and represents a potential target for therapeutic intervention. In this study, we characterized the mechanism underlying the protein kinase B (Akt) and c-Jun N-terminal kinase (JNK) pathways and BCMA interactions in regulating multiple myeloma (MM) cell survival. It was found that the expression levels of B cell-activating factor (BAFF) and BCMA were increased in MM cells as compared with those in normal controls. The proliferation of U266 cells was induced by recombinant human BAFF (rhBAFF) and could also be decreased by BCMA siRNA. The expression of Bcl-2 protein was up-regulated, and Bax protein was down-regulated after rhBAFF treatment, which could be reversed by BCMA siRNA. Similarly, the protein p-JNK and p-Akt were activated by rhBAFF and could be changed by BCMA siRNA. In addition, the BCMA mRNA and protein expression levels were decreased after treatment with Akt and JNK pathway inhibitors. These results suggest that Akt and JNK pathways are involved in the regulation of BCMA. A novel BAFF/BCMA signalling pathway in MM may be a new therapeutic target for MM.

Effective Targeting of Multiple B-Cell Maturation Antigen–Expressing Hematological Malignances by Anti-B-Cell Maturation Antigen Chimeric Antigen Receptor T Cells

“…19 BCMA signaling promotes MM survival via AKT1, mitogen-activated protein kinase (MAPK), and the nuclear factor (NF)-jB pathways, and recent reports further suggest that in the bonemarrow microenvironment of MM, BCMA signaling upregulates immune inhibitory molecules such as programmed death ligand (PD-L)1, IL-10, and transforming growth factor (TGF)-b. 38,39 BCMAtargeting antibody drug conjugates (ADC), bispecific BCMA/CD3 antibodies, and BCMA-targeted CAR T cells have all been reported to have anti-MM cell reactivity. 23,26,40,41 Recently, in a study of anti-BCMA bi-specific antibodies, Lee et al used ABCbead quantitation methods to determine BCMA receptor density on 39 MM patient samples.…”

Transcriptome Analysis of B Cell Immune Functions in Periodontitis: Mucosal Tissue Responses to the Oral Microbiome in Aging

“…It is essential, as part of the B cell receptor signaling pathway, for the response of B-cells to antigens and required for the formation of germinal centers ( 84 , 85 ). TNFRSF17 is a member of the TNF receptor superfamily and binds B cell activating factor (BAFF; TNFSF13B), which is expressed in B lineage cells resulting in potent B cell activation, as well as NF-κB and MAPK8/JNK activation ( 86 , 87 ). It is preferentially expressed on mature B cells and ligand engagement contributes to proliferation and differentiation of the B cells ( 78 , 88 ).…”

Targeting B Cell Maturation Antigen (BCMA) in Multiple Myeloma: Potential Uses of BCMA-Based Immunotherapy

“…Conversely, BCMA knockdown blocks MM cell proliferation and viability via downregulation of cell cycle progression and antiapoptosis molecules. APRIL and BAFF, via binding to BCMA and TACI, further activate NFκB pathways and upregulate antiapoptotic proteins (Mcl-1, Bcl-2, Bcl-xL) to protect MM cells against dexamethasone- and serum deprivation-induced cell death ( 31 , 58 , 59 ) (Figure 1 ). These studies establish a pathophysiological role of BCMA and APRIL in MM.…”