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J Clin Invest DOI:10.1172/JCI46465

The intersection of genetic and chemical genomic screens identifies GSK-3α as a target in human acute myeloid leukemia.

Publication TypeJournal Article
Year of Publication2012
AuthorsBanerji, V, Frumm, SM, Ross, KN, Li, LS, Schinzel, AC, Hahn, CK, Kakoza, RM, Chow, KT, Ross, L, Alexe, G, Tolliday, N, Inguilizian, H, Galinsky, I, Stone, RM, DeAngelo, DJ, Roti, G, Aster, JC, Hahn, WC, Kung, AL, Stegmaier, K
JournalJ Clin Invest
Volume122
Issue3
Pages935-47
Date Published2012 Mar
ISSN1558-8238
KeywordsCell Differentiation, Cell Proliferation, Cell Survival, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Genomics, Glycogen Synthase Kinase 3, HL-60 Cells, Humans, Leukemia, Myeloid, Acute, Neoplasms, RNA Interference, Technology, Pharmaceutical, U937 Cells
Abstract

Acute myeloid leukemia (AML) is the most common form of acute leukemia in adults. Long-term survival of patients with AML has changed little over the past decade, necessitating the identification and validation of new AML targets. Integration of genomic approaches with small-molecule and genetically based high-throughput screening holds the promise of improved discovery of candidate targets for cancer therapy. Here, we identified a role for glycogen synthase kinase 3α (GSK-3α) in AML by performing 2 independent small-molecule library screens and an shRNA screen for perturbations that induced a differentiation expression signature in AML cells. GSK-3 is a serine-threonine kinase involved in diverse cellular processes, including differentiation, signal transduction, cell cycle regulation, and proliferation. We demonstrated that specific loss of GSK-3α induced differentiation in AML by multiple measurements, including induction of gene expression signatures, morphological changes, and cell surface markers consistent with myeloid maturation. GSK-3α-specific suppression also led to impaired growth and proliferation in vitro, induction of apoptosis, loss of colony formation in methylcellulose, and anti-AML activity in vivo. Although the role of GSK-3β has been well studied in cancer development, these studies support a role for GSK-3α in AML.

DOI10.1172/JCI46465
Pubmed

http://www.ncbi.nlm.nih.gov/pubmed/22326953?dopt=Abstract

Alternate JournalJ. Clin. Invest.
PubMed ID22326953
PubMed Central IDPMC3287215
Grant ListR01 CA140292 / CA / NCI NIH HHS / United States
/ / Howard Hughes Medical Institute / United States