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

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 KB (NF kappa B)mediated expression of antlapoptotic molecules. Recent evidence indicates that glycogen synthase kinase-30 (GSK-3 beta) positively regulates NF kappa B-mediated gene transcription and cell survival. Using malignant B cells collected from patients with CLL, we find that both GSK-3 beta and NF kappa B accumulate in the nucleus of CLL B cells, and pharmacologic inhibition of GSK-3 results In decreased expression of two NF kappa B target genes Bc1-2 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 kappa B-mediated gene transcription but does not affect the nuclear accumulation of NF kappa B in CLL B cells. Last, using chromatin immunoprecipitation, we show that GSK-3 inhibition abrogates NF kappa 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 kappa 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.