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Glycogen synthase kinase 3 in MLL leukaemia maintenance and targeted therapy

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.

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Figure 1: Sensitivity of MLL leukaemia cell lines to GSK3 inhibition.
Figure 2: Sensitivity of MLL -transformed mouse B and myeloid progenitors to GSK3 inhibition.
Figure 3: Genetic ablation of GSK3-β hypersensitizes MLL -transformed cells to pharmacological GSK3 inhibition.
Figure 4: Compound genetic deficiency of GSK3-α and GSK3-β impairs the growth and leukemogenicity of MLL -transformed cells.
Figure 5: GSK3 maintains MLL transformation through suppression of p27Kip1.

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Acknowledgements

We thank R. Roth for providing AKT constructs, P. J. Roach for providing GSK3 constructs, D. G. Gilliland for providing a TEL-AML1 construct, M. Iwasaki for NUP98-HOXA9 cells, M. Ambrus and C. Nicolas for technical assistance, and members of the Cleary laboratory for discussions. We acknowledge support from the Children’s Health Initiative of the Packard Foundation, PHS grants CA55029 and CA116606, the Leukemia and Lymphoma Society, the Williams Lawrence Foundation and a Developmental Research Award from the Stanford Cancer Center.

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Correspondence to Michael L. Cleary.

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Wang, Z., Smith, K., Murphy, M. et al. Glycogen synthase kinase 3 in MLL leukaemia maintenance and targeted therapy. Nature 455, 1205–1209 (2008). https://doi.org/10.1038/nature07284

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