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Blood, 15 January 2007, Vol. 109, No. 2, pp. 703-710. Prepublished online as a Blood First Edition Paper on September 14, 2006; DOI 10.1182/blood-2006-06-027755. This Article Full Text (PDF) All Versions of this Article: blood-2006-06-027755v1 109/2/703    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Endo, T. Articles by Kipps, T. J. Search for Related Content PubMed PubMed Citation Articles by Endo, T. Articles by Kipps, T. J. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted June 9, 2006 Accepted August 27, 2006 BAFF And APRIL Support Chronic Lymphocytic Leukemia B Cell Survival Through Activation Of The Canonical NF-B Pathway Tomoyuki Endo, Mitsufumi Nishio, Thomas Enzler, Howard B. Cottam, Tetsuya Fukuda, Danelle F. James, Michael Karin, and Thomas J. Kipps* Moores Cancer Center, University of California, San Diego, La Jolla, CA Dept of Pharmacology, School of Medicine, University of California, San Diego, La Jolla, CA * Corresponding author; email: tkipps{at}ucsd.edu. 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 two 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-B) pathway in CLL cells, whereas signaling via 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 beta (IKK), or transfection of CLL cells with the IB super-repressor, blocked the capacity of BAFF and/or APRIL to promote CLL cell survival in vitro. This contrasts what is found with normal blood B cells, which apparently depend upon activation of the alternative NF-B pathway for BAFF-enhanced survival. These findings suggest that inhibitors of the protein kinase IKK, which is required for activation of the canonical NF-B pathway, might have therapeutic utility in this disease. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? 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