through activation of the canonical NF-B 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 cal-cium modulator and cyclophilin ligand-interactor (TACI), which also bind a prolif-eration-inducing ligand (APRIL). We found that signaling through BR3, but not BCMA or TACI, activated the alternative nuclear factor of B (NF-B) pathway in CLL cells, whereas signaling through BCMA/ TACI induced activation of the canonical NF-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-B pathway with UTC, an inhibitor of IB kinase (IKK), or transfection of CLL cells with the IB 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 acti-vation of the alternative NF-B pathway for BAFF-enhanced survival. These find-ings suggest that inhibitors of protein kinase IKK, which is required for activa-tion of the canonical NF-B pathway, might have a therapeutic role in this dis-ease. (Blood. 2007;109:703-710) © 2007 by The American Society of Hematolog