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J Clin Invest. 2012 Mar 1;122(3):935-47. doi: 10.1172/JCI46465. Epub 2012 Feb 13.

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

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  • 1Department of Pediatric Oncology, Dana-Farber Cancer Institute, Division of Hematology/Oncology, Children’s Hospital Boston, Boston 02215, Massachusetts, USA.

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.

PMID:
22326953
[PubMed - indexed for MEDLINE]
PMCID:
PMC3287215
Free PMC Article

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