Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

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.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

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.

References

  1. Doble, B. W. & Woodgett, J. R. GSK-3: tricks of the trade for a multi-tasking kinase. J. Cell Sci. 116, 1175–1186 (2003)

    CAS  Article  Google Scholar 

  2. Kim, L. & Kimmel, A. R. GSK3 at the edge: regulation of developmental specification and cell polarization. Curr. Drug Targets 7, 1411–1419 (2006)

    CAS  Article  Google Scholar 

  3. Cohen, P. & Frame, S. The renaissance of GSK3. Nature Rev. Mol. Cell Biol. 2, 769–776 (2001)

    CAS  Article  Google Scholar 

  4. Fiol, C. J., Mahrenholz, A. M., Wang, Y., Roeske, R. W. & Roach, P. J. Formation of protein kinase recognition sites by covalent modification of the substrate. Molecular mechanism for the synergistic action of casein kinase II and glycogen synthase kinase 3. J. Biol. Chem. 262, 14042–14048 (1987)

    CAS  PubMed  Google Scholar 

  5. Cross, D. A., Alessi, D. R., Cohen, P., Andjelkovich, M. & Hemmings, B. A. Inhibition of glycogen synthase kinase-3 by insulin mediated by protein kinase B. Nature 378, 785–789 (1995)

    ADS  CAS  Article  Google Scholar 

  6. Kaidanovich, O. & Eldar-Finkelman, H. The role of glycogen synthase kinase-3 in insulin resistance and type 2 diabetes. Expert Opin. Ther. Targets 6, 555–561 (2002)

    CAS  Article  Google Scholar 

  7. Hoeflich, K. P. et al. Requirement for glycogen synthase kinase-3β in cell survival and NF-κB activation. Nature 406, 86–90 (2000)

    ADS  CAS  Article  Google Scholar 

  8. Martin, M., Rehani, K., Jope, R. S. & Michalek, S. M. Toll-like receptor-mediated cytokine production is differentially regulated by glycogen synthase kinase 3. Nature Immunol. 6, 777–784 (2005)

    CAS  Article  Google Scholar 

  9. De Ferrari, G. V. & Inestrosa, N. C. Wnt signaling function in Alzheimer’s disease. Brain Res. Rev. 33, 1–12 (2000)

    CAS  Article  Google Scholar 

  10. Miller, J. R. & Moon, R. T. Signal transduction through β-catenin and specification of cell fate during embryogenesis. Genes Dev. 10, 2527–2539 (1996)

    CAS  Article  Google Scholar 

  11. Jia, J. et al. Shaggy/GSK3 antagonizes Hedgehog signalling by regulating Cubitus interruptus. Nature 416, 548–552 (2002)

    ADS  CAS  Article  Google Scholar 

  12. Miller, J. R. The Wnts. Genome Biol 3, 3001 (2002)

    Google Scholar 

  13. Yost, C. et al. The axis-inducing activity, stability, and subcellular distribution of β-catenin is regulated in Xenopus embryos by glycogen synthase kinase 3. Genes Dev. 10, 1443–1454 (1996)

    CAS  Article  Google Scholar 

  14. van Noort, M., Meeldijk, J., van der Zee, R., Destree, O. & Clevers, H. Wnt signaling controls the phosphorylation status of β-catenin. J. Biol. Chem. 277, 17901–17905 (2002)

    CAS  Article  Google Scholar 

  15. Sears, R. et al. Multiple Ras-dependent phosphorylation pathways regulate Myc protein stability. Genes Dev. 14, 2501–2514 (2000)

    ADS  CAS  Article  Google Scholar 

  16. Nikolakaki, E., Coffer, P. J., Hemelsoet, R., Woodgett, J. R. & Defize, L. H. Glycogen synthase kinase 3 phosphorylates Jun family members in vitro and negatively regulates their transactivating potential in intact cells. Oncogene 8, 833–840 (1993)

    CAS  PubMed  Google Scholar 

  17. Trowbridge, J. J., Xenocostas, A., Moon, R. T. & Bhatia, M. Glycogen synthase kinase-3 is an in vivo regulator of hematopoietic stem cell repopulation. Nature Med. 12, 89–98 (2006)

    CAS  Article  Google Scholar 

  18. Sato, N., Meijer, L., Skaltsounis, L., Greengard, P. & Brivanlou, A. H. Maintenance of pluripotency in human and mouse embryonic stem cells through activation of Wnt signaling by a pharmacological GSK-3-specific inhibitor. Nature Med. 10, 55–63 (2004)

    CAS  Article  Google Scholar 

  19. Ayton, P. M. & Cleary, M. L. Molecular mechanisms of leukemogenesis mediated by MLL fusion proteins. Oncogene 20, 5695–5707 (2001)

    CAS  Article  Google Scholar 

  20. Hess, J. L. MLL: a histone methyltransferase disrupted in leukemia. Trends Mol. Med. 10, 500–507 (2004)

    CAS  Article  Google Scholar 

  21. Lavau, C., Szilvassy, S. J., Slany, R. & Cleary, M. L. Immortalization and leukemic transformation of a myelomonocytic precursor by retrovirally transduced HRX-ENL. EMBO J. 16, 4226–4237 (1997)

    CAS  Article  Google Scholar 

  22. Somervaille, T. C. & Cleary, M. L. Identification and characterization of leukemia stem cells in murine MLL-AF9 acute myeloid leukemia. Cancer Cell 10, 257–268 (2006)

    CAS  Article  Google Scholar 

  23. Watase, K. et al. Lithium therapy improves neurological function and hippocampal dendritic arborization in a spinocerebellar ataxia type 1 mouse model. PLoS Med. 4, e182 (2007)

    Article  Google Scholar 

  24. Polakis, P. The oncogenic activation of beta-catenin. Curr. Opin. Genet. Dev. 9, 15–21 (1999)

    CAS  Article  Google Scholar 

  25. Testa, J. R. & Tsichlis, P. N. AKT signaling in normal and malignant cells. Oncogene 24, 7391–7393 (2005)

    CAS  Article  Google Scholar 

  26. Nickeleit, I., Zender, S., Kossatz, U. & Malek, N. P. p27kip1: a target for tumor therapies? Cell Div. 2, 13 (2007)

    Article  Google Scholar 

  27. Milne, T. A. et al. Menin and MLL cooperatively regulate expression of cyclin-dependent kinase inhibitors. Proc. Natl Acad. Sci. USA 102, 749–754 (2005)

    ADS  CAS  Article  Google Scholar 

  28. Yokoyama, A. et al. The menin tumor suppressor protein is an essential oncogenic cofactor for MLL-associated leukemogenesis. Cell 123, 207–218 (2005)

    CAS  Article  Google Scholar 

  29. Hughes, C. M. et al. Menin associates with a trithorax family histone methyltransferase complex and with the Hoxc8 locus. Mol. Cell 13, 587–597 (2004)

    CAS  Article  Google Scholar 

  30. Xia, Z. B. et al. The MLL fusion gene, MLLAF4, regulates cyclin-dependent kinase inhibitor CDKN1B (p27kip1) expression. Proc. Natl Acad. Sci. USA 102, 14028–14033 (2005)

    ADS  CAS  Article  Google Scholar 

  31. Surjit, M. & Lal, S. K. Glycogen synthase kinase-3 phosphorylates and regulates the stability of p27kip1 protein. Cell Cycle 6, 580–588 (2007)

    CAS  Article  Google Scholar 

  32. G.-Amlak, M. et al. Regulation of myeloma cell growth through Akt/Gsk3/forkhead signaling pathway. Biochem. Biophys. Res. Commun. 297, 760–764 (2002)

    CAS  Article  Google Scholar 

  33. Dimartino, J. F. & Cleary, M. L. Mll rearrangements in haematological malignancies: lessons from clinical and biological studies. Br. J. Haematol. 106, 614–626 (1999)

    CAS  Article  Google Scholar 

  34. Chen, C. S. et al. Molecular rearrangements on chromosome 11q23 predominate in infant acute lymphoblastic leukemia and are associated with specific biologic variables and poor outcome. Blood 81, 2386–2393 (1993)

    CAS  PubMed  Google Scholar 

  35. Gould, T. D. & Manji, H. K. The Wnt signaling pathway in bipolar disorder. Neuroscientist 8, 497–511 (2002)

    CAS  Article  Google Scholar 

  36. Yilmaz, O. H. et al. Pten dependence distinguishes haematopoietic stem cells from leukaemia-initiating cells. Nature 441, 475–482 (2006)

    ADS  CAS  Article  Google Scholar 

  37. Smith, K. S., Rhee, J. W. & Cleary, M. L. Transformation of bone marrow B-cell progenitors by E2A-HlF requires coexpression of BCL-2. Mol. Cell. Biol. 22, 7678–7687 (2002)

    CAS  Article  Google Scholar 

  38. So, C. W. et al. MLL-GAS7 transforms multipotent hematopoietic progenitors and induces mixed lineage leukemias in mice. Cancer Cell 3, 161–171 (2003)

    CAS  Article  Google Scholar 

  39. Smith, K. S., Jacobs, Y., Chang, C. P. & Cleary, M. L. Chimeric oncoprotein E2a-Pbx1 induces apoptosis of hematopoietic cells by a p53-independent mechanism that is suppressed by Bcl-2. Oncogene 14, 2917–2926 (1997)

    CAS  Article  Google Scholar 

  40. Kasper, L. H. et al. CREB binding protein interacts with nucleoporin-specific FG repeats that activate transcription and mediate NUP98-HOXA9 oncogenicity. Mol. Cell. Biol. 19, 764–776 (1999)

    CAS  Article  Google Scholar 

  41. Kohn, A. D. et al. Construction and characterization of a conditionally active version of the serine/threonine kinase Akt. J. Biol. Chem. 273, 11937–11943 (1998)

    CAS  Article  Google Scholar 

  42. So, C. W. & Cleary, M. L. MLL-AFX requires the transcriptional effector domains of AFX to transform myeloid progenitors and transdominantly interfere with forkhead protein function. Mol. Cell. Biol. 22, 6542–6552 (2002)

    CAS  Article  Google Scholar 

  43. Ventura, A. et al. Cre-lox-regulated conditional RNA interference from transgenes. Proc. Natl Acad. Sci. USA 101, 10380–10385 (2004)

    ADS  CAS  Article  Google Scholar 

Download references

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.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Michael L. Cleary.

Supplementary information

Supplementary Information

This file contains Supplementary Figures and Legends 1-8 and Supplementary Tables 1-3. (PDF 1483 kb)

PowerPoint slides

Rights and permissions

Reprints and Permissions

About this article

Cite this article

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

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature07284

Further reading

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing