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.
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.
Ougolkov
Andrei V
AV
Division of Oncology Research, Mayo Clinic College of Medicine, Rochester, MN, USA.
Bone
Nancy D
ND
Fernandez-Zapico
Martin E
ME
Kay
Neil E
NE
Billadeau
Daniel D
DD
D017209:Apoptosis; D001402:B-Lymphocytes / Q000473:pathology*; D002843:Chromatin / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors*; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics* / Q000473:pathology; D008214:Lymphocytes / Q000473:pathology / Q000502:physiology; D016328:NF-kappa B / Q000502:physiology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics; D012016:Reference Values; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000235:genetics
D002843:Chromatin; D016328:NF-kappa B; D019253:Proto-Oncogene Proteins c-bcl-2; D051636:X-Linked Inhibitor of Apoptosis Protein; D038362:Glycogen Synthase Kinase 3