BAFF and APRIL support chronic lymphocytic leukemia B-cell survival through activation of the canonical NF-κB pathway

Chronic lymphocytic leukemia (CLL) B cells express BR3, the specific receptor for the B cell-activating factor of tumor necrosis factor family (BAFF). CLL cells also express 2 other receptors for BAFF, namely B-cell maturation antigen (BCMA) and the transmembrane activator and calcium modulator and cyclophilin ligand-interactor (TACI), which also bind a proliferation-inducing ligand (APRIL). We found that signaling through BR3, but not BCMA or TACI, activated the alternative nuclear factor of kappa B (NF-kappa B) pathway in CLL cells, whereas signaling through BCMA/ TACI induced activation of the canonical NF-kappa B pathway. Blocking BR3 did not inhibit the capacity of BAFF to support CLL cell survival in vitro. On the other hand, specifically blocking the canonical NF-kappa B pathway with LITC, an inhibitor of I kappa B kinase beta (IKK beta), or transfection of CLL cells with the I kappa B alpha super-repressor, blocked the capacity of BAFF and APRIL to promote CLL cell survival in vitro. This contrasts what is found with normal blood B cells, which apparently depend on activation of the alternative NF-kappa B pathway for BAFF-enhanced survival. These findings suggest that inhibitors of protein kinase IKK beta, which is required for activation of the canonical NF-kappa B pathway, might have a therapeutic role in this disease. (c) 2007 by The American Society of Hematology