Bhanot, HaymantiReddy, Mamatha M.Nonami, AtsushiWeisberg, EllenBonal, DennisKirschmeier, Paul T.Salgia, SabrinaPodar, KlausGalinsky, IleneChowdary, Tirumala K.Neuberg, DonnaTonon, GiovanniStone, RichardAsara, JohnGriffin, JamesSattler, Martin2016-02-012015Bhanot, H., M. M. Reddy, A. Nonami, E. L. Weisberg, D. Bonal, P. T. Kirschmeier, S. Salgia, et al. 2015. “Pathological glycogenesis through glycogen synthase 1 and suppression of excessive AMP kinase activity in myeloid leukemia cells.” Leukemia 29 (7): 1555-1563. doi:10.1038/leu.2015.46. http://dx.doi.org/10.1038/leu.2015.46.0887-6924http://nrs.harvard.edu/urn-3:HUL.InstRepos:24983946The 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 AMPK (AMP kinase), 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.en-USCMLAMLmetabolic reprogrammingsignal transductionglycogenJournal Article2016-02-0110.1038/leu.2015.46