BAFF and APRIL support chronic lymphocytic leukemia B-cell survival through activation of the canonical NF-κB pathway
Open Access
- 14 September 2006
- journal article
- Published by American Society of Hematology in Blood
- Vol. 109 (2), 703-710
- https://doi.org/10.1182/blood-2006-06-027755
Abstract
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 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.Keywords
This publication has 58 references indexed in Scilit:
- Synthetic anti-BR3 antibodies that mimic BAFF binding and target both human and murine B cellsBlood, 2006
- Role of BAFF and APRIL in human B‐cell chronic lymphocytic leukaemiaImmunology, 2006
- Nuclear factor-κB in cancer development and progressionNature, 2006
- A MicroRNA Signature Associated with Prognosis and Progression in Chronic Lymphocytic LeukemiaNew England Journal of Medicine, 2005
- The functions of animal microRNAsNature, 2004
- Attenuation of Murine Collagen-Induced Arthritis by a Novel, Potent, Selective Small Molecule Inhibitor of IκB Kinase 2, TPCA-1 (2-[(Aminocarbonyl)amino]-5-(4-fluorophenyl)-3-thiophenecarboxamide), Occurs via Reduction of Proinflammatory Cytokines and Antigen-Induced T Cell ProliferationJournal of Pharmacology and Experimental Therapeutics, 2004
- A sustained activation of PI3K/NF-κB pathway is critical for the survival of chronic lymphocytic leukemia B cellsLeukemia, 2004
- MicroRNAs: Genomics, Biogenesis, Mechanism, and FunctionCell, 2004
- BAFF-induced NEMO-independent processing of NF-κB2 in maturing B cellsNature Immunology, 2002
- Nuclear Factor (NF)-κB2 (p100/p52) Is Required for Normal Splenic Microarchitecture and B Cell–mediated Immune ResponsesThe Journal of Experimental Medicine, 1998