title: Pathological glycogenesis through glycogen synthase 1 and suppression of excessive AMP kinase activity in myeloid leukemia cells.
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.
authors.affiliation: Department of Medical Oncology, Boston, MA, 02215, USA.|Department of Medicine, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Haymanti
authors.initials: H
authors.lastname: Bhanot
authors.affiliation: Department of Medical Oncology, Boston, MA, 02215, USA.|Department of Medicine, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Mamatha M
authors.initials: MM
authors.lastname: Reddy
authors.affiliation: Department of Medical Oncology, Boston, MA, 02215, USA.|Department of Medicine, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Nonami
authors.affiliation: Department of Medical Oncology, Boston, MA, 02215, USA.|Department of Medicine, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Ellen L
authors.initials: EL
authors.lastname: Weisberg
authors.affiliation: Center for Biomedical Imaging in Oncology (CBIO), Lurie Family Imaging Center (LFIC), Boston, MA, 02215, USA.
authors.forename: Dennis
authors.initials: D
authors.lastname: Bonal
authors.affiliation: Center for Biomedical Imaging in Oncology (CBIO), Lurie Family Imaging Center (LFIC), Boston, MA, 02215, USA.
authors.forename: Paul T
authors.initials: PT
authors.lastname: Kirschmeier
authors.affiliation: Department of Medical Oncology, Boston, MA, 02215, USA.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Salgia
authors.affiliation: National Center for Tumor Diseases (NCT), Heidelberg, Germany.|University of Heidelberg, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Klaus
authors.initials: K
authors.lastname: Podar
authors.affiliation: Department of Medical Oncology, Boston, MA, 02215, USA.
authors.forename: Ilene
authors.initials: I
authors.lastname: Galinsky
authors.affiliation: School of Biological Sciences, National Institute of Science Education & Research, Bhubaneswar, India.
authors.forename: Tirumala K
authors.initials: TK
authors.lastname: Chowdary
authors.affiliation: Department of Biostatistics and Computational Biology Dana-Farber Cancer Institute, Boston, MA, 02215, USA.
authors.forename: Donna
authors.initials: D
authors.lastname: Neuberg
authors.affiliation: San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Tonon
authors.affiliation: Department of Medical Oncology, Boston, MA, 02215, USA.|Department of Medicine, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Richard M
authors.initials: RM
authors.lastname: Stone
authors.affiliation: Department of Medicine, Harvard Medical School, Boston, MA 02215, USA.|Division of Signal Transduction/Mass Spectrometry Core, Beth Israel Deaconess Medical Center, Boston, MA02215, USA.
authors.forename: John
authors.initials: J
authors.lastname: Asara
authors.affiliation: Department of Medical Oncology, Boston, MA, 02215, USA.|Department of Medicine, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: James D
authors.initials: JD
authors.lastname: Griffin
authors.affiliation: Department of Medical Oncology, Boston, MA, 02215, USA.|Department of Medicine, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Martin
authors.initials: M
authors.lastname: Sattler
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis; D016022:Case-Control Studies; D049109:Cell Proliferation; D005434:Flow Cytometry; D006003:Glycogen / Q000096:biosynthesis*; D006006:Glycogen Synthase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D006019:Glycolysis; D057809:HEK293 Cells; D006801:Humans; D007951:Leukemia, Myeloid / Q000378:metabolism* / Q000401:mortality / Q000473:pathology*; D055432:Metabolomics; D051379:Mice; D010766:Phosphorylation; D011379:Prognosis; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015996:Survival Rate; D014407:Tumor Cells, Cultured
chemical_list: D012333:RNA, Messenger; D034741:RNA, Small Interfering; D006003:Glycogen; D006006:Glycogen Synthase; D055372:AMP-Activated Protein Kinases