Bcl-xL protects from UPR-associated apoptosis during plasma cell differentiation. (P1457)

Abstract

Abstract Understanding factors that control plasma cell survival is important for the development of therapeutic approaches to diseases including multiple myeloma and autoimmune disorders. Plasma cell differentiation requires activation of the unfolded protein response, a set of signaling pathways in which prolonged activation leads to apoptosis in other cell types. Plasma cells activate this pathway during differentiation suggesting compensatory survival signals are activated. Consistent with this hypothesis, we found that LPS-driven differentiation protects Bcl1 cells against tunicamycin-activated ER stress-induced death. LPS plus cytokine-induced differentiation was associated with an increase in Bcl-xL expression accompanied by a decrease in Mcl-1 or Bcl-2 in Bcl1 cells and primary B cells respectively. Moreover, differentiation-induced protection against ER stress was shown to be Bcl-xL-dependent as tunicamycin-induced death was restored by the addition of the Bcl-xL/Bcl-2 inhibitor, ABT-737. Importantly, we also showed that during differentiation, Bcl1 cells and primary B cells are Bcl-xL-dependent as ABT-737 resulted in significant apoptosis in the absence of any additional death signal. Finally, we found that differentiation was accompanied by a change in Bim binding from primarily Mcl-1 and/or Bcl-2 to Bcl-xL in differentiating cells. These data demonstrate that Bcl-xL induction protects from death signals activated during plasma cell differentiation.