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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.
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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 (NF B)-mediated expression of antiapoptotic molecules. Recent evidence indicates that glycogen synthase kinase-3ß (GSK-3ß) positively regulates NF B-mediated gene transcription and cell survival. Using malignant B cells collected from patients with CLL, we find that both GSK-3ß and NF B accumulate in the nucleus of CLL B cells, and pharmacologic inhibition of GSK-3 results in decreased expression of two NF B 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 NF B-mediated gene transcription but does not affect the nuclear accumulation of NF B in CLL B cells. Last, using chromatin immunoprecipitation, we show that GSK-3 inhibition abrogates NF B 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 NF B 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.

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