Inhibition of glycogen synthase kinase-3 activity leads to epigenetic silencing of nuclear factor κB target genes and induction of apoptosis in chronic lymphocytic leukemia B cells

Andrei V. Ougolkov, Nancy D. Bone, Martin E. Fernandez-Zapico, Neil E. Kay*, Daniel D. Billadeau

*Corresponding author for this work

Research output: Contribution to journalArticle

132 Scopus citations

Abstract

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

Original languageEnglish (US)
Pages (from-to)735-742
Number of pages8
JournalBlood
Volume110
Issue number2
DOIs
StatePublished - Jul 15 2007

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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