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- Title
The intersection of genetic and chemical genomic screens identifies GSK-3α as a target in human acute myeloid leukemia.
- Authors
Banerji, Versha; Frumm, Stacey M; Ross, Kenneth N; Li, Loretta S; Schinzel, Anna C; Hahn, Cynthia K; Kakoza, Rose M; Chow, Kwan T; Ross, Linda; Alexe, Gabriela; Tolliday, Nicola; Inguilizian, Haig; Galinsky, Ilene; Stone, Richard M; DeAngelo, Daniel J; Roti, Giovanni; Aster, Jon C; Hahn, William C; Kung, Andrew L; Stegmaier, Kimberly
- 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.
- Publication
The Journal of clinical investigation, 2012, Vol 122, Issue 3, p935
- ISSN
1558-8238
- Publication type
Journal Article
- DOI
10.1172/JCI46465