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

AbstractChronic 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 κ B (NF-κB) pathway in CLL cells, whereas signaling through BCMA/TACI induced activation of the canonical NF-κB 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-κB pathway with UTC, an inhibitor of IκB kinase β (IKKβ), or transfection of CLL cells with the IκBα 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-κB pathway for BAFF-enhanced survival. These findings suggest that inhibitors of protein kinase IKKβ, which is required for activation of the canonical NF-κB pathway, might have a therapeutic role in this disease.