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Blood, 15 July 2007, Vol. 110, No. 2, pp. 735-742. Prepublished online as a Blood First Edition Paper on April 26, 2007; DOI 10.1182/blood-2006-12-060947. This Article Full Text Full Text (PDF) All Versions of this Article: blood-2006-12-060947v1 110/2/735    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map 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 Ougolkov, A. V. Articles by Billadeau, D. D. Search for Related Content PubMed PubMed Citation Articles by Ougolkov, A. V. Articles by Billadeau, D. D. Related Collections Apoptosis Gene Expression Neoplasia Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  NEOPLASIA Inhibition of glycogen synthase kinase-3 activity leads to epigenetic silencing of nuclear factor B target genes and induction of apoptosis in chronic lymphocytic leukemia B cells Andrei V. Ougolkov1, Nancy D. Bone2, Martin E. Fernandez-Zapico3, Neil E. Kay2, and Daniel D. Billadeau1 Divisions of1 Oncology Research and 2 Hematology and 3 Gastroenterology Research Unit, Mayo Clinic College of Medicine, Rochester, MN Chronic lymphocytic leukemia (CLL) is commonly defined as a disease of failed apoptosis of B cells and remains an incurable disease. The mechanism of resistance to apoptosis in CLL is complex and influenced by numerous factors, including nuclear factor B (NFB)-mediated expression of antiapoptotic molecules. Recent evidence indicates that glycogen synthase kinase-3ß (GSK-3ß) positively regulates NFB-mediated gene transcription and cell survival. Using malignant B cells collected from patients with CLL, we find that both GSK-3ß and NFB accumulate in the nucleus of CLL B cells, and pharmacologic inhibition of GSK-3 results in decreased expression of two NFB target genes Bcl-2 and XIAP and a subsequent increase in CLL B-cell apoptosis ex vivo. Furthermore, we observed that inhibition of GSK-3 leads to a decrease in NFB-mediated gene transcription but does not affect the nuclear accumulation of NFB in CLL B cells. Last, using chromatin immunoprecipitation, we show that GSK-3 inhibition abrogates NFB binding to its target gene promoters (XIAP, Bcl-2), in part through epigenetic modification of histones. Our results establish that inhibition of GSK-3 abrogates NFB binding to its target gene promoters through an epigenetic mechanism, enhances apoptosis in CLL B cells ex vivo and identifies GSK-3 as a potential therapeutic target in the treatment of CLL. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: M. Muzio, B. Apollonio, C. Scielzo, M. Frenquelli, I. Vandoni, V. Boussiotis, F. Caligaris-Cappio, and P. Ghia Constitutive activation of distinct BCR-signaling pathways in a subset of CLL patients: a molecular signature of anergy Blood, July 1, 2008; 112(1): 188 - 195. [Abstract] [Full Text] [PDF] T. Holmes, T. A. O'Brien, R. Knight, R. Lindeman, S. Shen, E. Song, G. Symonds, and A. Dolnikov Glycogen Synthase Kinase-3{beta} Inhibition Preserves Hematopoietic Stem Cell Activity and Inhibits Leukemic Cell Growth Stem Cells, May 1, 2008; 26(5): 1288 - 1297. [Abstract] [Full Text] [PDF] R. Gong, A. Rifai, Y. Ge, S. Chen, and L. D. Dworkin Hepatocyte Growth Factor Suppresses Proinflammatory NF{kappa}B Activation through GSK3{beta} Inactivation in Renal Tubular Epithelial Cells J. Biol. Chem., March 21, 2008; 283(12): 7401 - 7410. [Abstract] [Full Text] [PDF]

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