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

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

• Authors: Andrei V Ougolkov, Nancy D Bone, Martin E Fernandez-Zapico, Neil E Kay, Daniel D Billadeau
• Journal: Blood (Blood) Vol. 110 Issue 2 Pg. 735-42 (Jul 15 2007) ISSN: 0006-4971 [Print] United States
• PMID: 17463171 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Chromatin
• NF-kappa B
• Proto-Oncogene Proteins c-bcl-2
• X-Linked Inhibitor of Apoptosis Protein
• Glycogen Synthase Kinase 3

Topics

• Apoptosis
• B-Lymphocytes (pathology)
• Chromatin (genetics)
• Gene Expression Regulation, Neoplastic
• Gene Silencing
• Glycogen Synthase Kinase 3 (antagonists & inhibitors)
• Humans
• Leukemia, Lymphocytic, Chronic, B-Cell (genetics, pathology)
• Lymphocytes (pathology, physiology)
• NF-kappa B (physiology)
• Proto-Oncogene Proteins c-bcl-2 (genetics)
• Reference Values
• Reverse Transcriptase Polymerase Chain Reaction
• X-Linked Inhibitor of Apoptosis Protein (genetics)