BAFF and APRIL protect myeloma cells from apoptosis induced by IL-6 deprivation and dexamethasone

Identification of growth factors in neoplasias may be a target for future therapies by blocking either growth factor–receptor interaction or the induced pathway. Using gene expression profiling, we identified overexpression of two receptors for APRIL and BAFF in malignant plasma cells compared to normal plasma cells. APRIL and BAFF are involved in a variety of tumor and autoimmune diseases, including B-cell malignancies. We confirmed the expression of BAFF and APRIL receptors (BCMA, TACI and BAFF-R) in a majority of 13 myeloma cell lines and in the purified primary myeloma cells of 11 patients. APRIL and BAFF were potent survival factors for exogenous cytokine-dependent myeloma cell lines and were autocrine growth factors for the RPMI8226 and L363 autonomously growing cell lines. These factors activated NF-κB, phosphatidylinositol-3 kinase/AKT and MAPK kinase pathways and induced a strong upregulation of the Mcl-1 and Bcl-2 antiapoptotic proteins in myeloma cells. BAFF or APRIL was also involved in the survival of primary myeloma cells cultured with their bone-marrow environment and protected them from DEX-induced apoptosis. Finally, serum levels of BAFF and APRIL were increased about five fold in patients with MM as compared to healthy donors. Altogether, these data suggest that APRIL/BAFF inhibitors may be of clinical value in MM.