Glycogen synthase kinase 3 in MLL leukaemia maintenance and targeted therapy

Zhong Wang, Kevin S. Smith, Mark Murphy, Obdulio Piloto, Tim C. P. Somervaille and Michael L. Cleary ()
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Zhong Wang: Stanford University School of Medicine, Stanford, California 94305, USA
Kevin S. Smith: Stanford University School of Medicine, Stanford, California 94305, USA
Mark Murphy: Stanford University School of Medicine, Stanford, California 94305, USA
Obdulio Piloto: Stanford University School of Medicine, Stanford, California 94305, USA
Tim C. P. Somervaille: Stanford University School of Medicine, Stanford, California 94305, USA
Michael L. Cleary: Stanford University School of Medicine, Stanford, California 94305, USA

Nature, 2008, vol. 455, issue 7217, 1205-1209

Abstract: 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 p27Kip1. 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.

Date: 2008
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DOI: 10.1038/nature07284

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