Abstract
Glycogen synthase kinase 3 (GSK3) is a multifunctional serine/threonine kinase that participates in numerous signalling pathways involved in diverse physiological processes. Several of these pathways are implicated in disease pathogenesis, which has prompted efforts to develop GSK3-specific inhibitors for therapeutic applications. However, before now, there has been no strong rationale for targeting GSK3 in malignancies. Here we report pharmacological, physiological and genetic studies that demonstrate an oncogenic requirement for GSK3 in the maintenance of a specific subtype of poor prognosis human leukaemia, genetically defined by mutations of the MLL proto-oncogene. In contrast to its previously characterized roles in suppression of neoplasia-associated signalling pathways, GSK3 paradoxically supports MLL leukaemia cell proliferation and transformation by a mechanism that ultimately involves destabilization of the cyclin-dependent kinase inhibitor p27(Kip1). Inhibition of GSK3 in a preclinical murine model of MLL leukaemia provides promising evidence of efficacy and earmarks GSK3 as a candidate cancer drug target.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Cell Division
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Cell Line, Transformed
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Cell Line, Tumor
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Cell Proliferation
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Cell Transformation, Neoplastic*
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Cyclin-Dependent Kinase Inhibitor p27
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Disease Models, Animal
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G1 Phase
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Glycogen Synthase Kinase 3 / antagonists & inhibitors
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Glycogen Synthase Kinase 3 / deficiency
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Glycogen Synthase Kinase 3 / genetics
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Glycogen Synthase Kinase 3 / metabolism*
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Histone-Lysine N-Methyltransferase
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Humans
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Intracellular Signaling Peptides and Proteins / antagonists & inhibitors
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Intracellular Signaling Peptides and Proteins / metabolism
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Isoenzymes / metabolism
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Leukemia, Lymphoid / drug therapy*
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Leukemia, Lymphoid / enzymology
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Leukemia, Lymphoid / metabolism
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Leukemia, Lymphoid / pathology*
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Mice
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Mice, Inbred C57BL
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Mice, SCID
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Myeloid Progenitor Cells / enzymology
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Myeloid Progenitor Cells / metabolism
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Myeloid Progenitor Cells / pathology
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Myeloid-Lymphoid Leukemia Protein / metabolism*
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Precursor Cells, B-Lymphoid / enzymology
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Precursor Cells, B-Lymphoid / metabolism
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Precursor Cells, B-Lymphoid / pathology
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Proto-Oncogene Mas
Substances
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CDKN1B protein, human
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Intracellular Signaling Peptides and Proteins
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Isoenzymes
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KMT2A protein, human
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MAS1 protein, human
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Proto-Oncogene Mas
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Cyclin-Dependent Kinase Inhibitor p27
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Myeloid-Lymphoid Leukemia Protein
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Histone-Lysine N-Methyltransferase
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Glycogen Synthase Kinase 3