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Transcriptional Control and Signal Transduction

Pathological glycogenesis through glycogen synthase 1 and suppression of excessive AMP kinase activity in myeloid leukemia cells

Leukemia volume 29, pages 1555–1563 (2015)Cite this article

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Abstract

The rapid proliferation of myeloid leukemia cells is highly dependent on increased glucose metabolism. Through an unbiased metabolomics analysis of leukemia cells, we found that the glycogenic precursor UDP-D-glucose is pervasively upregulated, despite low glycogen levels. Targeting the rate-limiting glycogen synthase 1 (GYS1) not only decreased glycolytic flux but also increased activation of the glycogen-responsive AMP kinase (AMPK), leading to significant growth suppression. Further, genetic and pharmacological hyper-activation of AMPK was sufficient to induce the changes observed with GYS1 targeting. Cancer genomics data also indicate that elevated levels of the glycogenic enzymes GYS1/2 or GBE1 (glycogen branching enzyme 1) are associated with poor survival in AML. These results suggest a novel mechanism whereby leukemic cells sustain aberrant proliferation by suppressing excess AMPK activity through elevated glycogenic flux and provide a therapeutic entry point for targeting leukemia cell metabolism.

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Acknowledgements

This work is supported in part by National Institutes of Health grant CA134660 (MS), CA6696 (JDG) and by the Gloria Spivak Faculty Advancement Fund (MS).

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Author notes

  1. M M Reddy

    Present address: 11Current address: LV Prasad Eye Institute, Bhubaneswar, India.,

  2. H Bhanot and M M Reddy: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA

    H Bhanot, M M Reddy, A Nonami, E L Weisberg, S Salgia, I Galinsky, R M Stone, J D Griffin & M Sattler

  2. Department of Medicine, Harvard Medical School, Boston, MA, USA

    H Bhanot, M M Reddy, A Nonami, E L Weisberg, R M Stone, J Asara, J D Griffin & M Sattler

  3. Center for Biomedical Imaging in Oncology (CBIO), Lurie Family Imaging Center (LFIC), Dana-Farber Cancer Institute, Boston, MA, USA

    D Bonal & P T Kirschmeier

  4. National Center for Tumor Diseases (NCT), Heidelberg, Germany

    K Podar

  5. University of Heidelberg, German Cancer Research Center (DKFZ), Heidelberg, Germany

    K Podar

  6. School of Biological Sciences, National Institute of Science Education and Research, Bhubaneswar, India

    T K Chowdary

  7. Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA, USA

    D Neuberg

  8. San Raffaele Scientific Institute, Milan, Italy

    G Tonon

  9. Division of Signal Transduction/Mass Spectrometry Core, Beth Israel Deaconess Medical Center, Boston, MA, USA

    J Asara

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  1. H Bhanot
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Bhanot, H., Reddy, M., Nonami, A. et al. Pathological glycogenesis through glycogen synthase 1 and suppression of excessive AMP kinase activity in myeloid leukemia cells. Leukemia 29, 1555–1563 (2015). https://doi.org/10.1038/leu.2015.46

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