title: AMPK Is Essential to Balance Glycolysis and Mitochondrial Metabolism to Control T-ALL Cell Stress and Survival.
abstract: T cell acute lymphoblastic leukemia (T-ALL) is an aggressive malignancy associated with Notch pathway mutations. While both normal activated and leukemic T cells can utilize aerobic glycolysis to support proliferation, it is unclear to what extent these cell populations are metabolically similar and if differences reveal T-ALL vulnerabilities. Here we show that aerobic glycolysis is surprisingly less active in T-ALL cells than proliferating normal T cells and that T-ALL cells are metabolically distinct. Oncogenic Notch promoted glycolysis but also induced metabolic stress that activated 5' AMP-activated kinase (AMPK). Unlike stimulated T cells, AMPK actively restrained aerobic glycolysis in T-ALL cells through inhibition of mTORC1 while promoting oxidative metabolism and mitochondrial Complex I activity. Importantly, AMPK deficiency or inhibition of Complex I led to T-ALL cell death and reduced disease burden. Thus, AMPK simultaneously inhibits anabolic growth signaling and is essential to promote mitochondrial pathways that mitigate metabolic stress and apoptosis in T-ALL.
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke University, Durham, NC 27710, USA; Department of Immunology, Duke University, Durham, NC 27710, USA; Duke Molecular Physiology Institute, Duke University, Durham, NC 27710, USA.
authors.forename: Rigel J
authors.initials: RJ
authors.lastname: Kishton
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke University, Durham, NC 27710, USA.
authors.forename: Carson E
authors.initials: CE
authors.lastname: Barnes
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke University, Durham, NC 27710, USA; Department of Immunology, Duke University, Durham, NC 27710, USA; Duke Molecular Physiology Institute, Duke University, Durham, NC 27710, USA.
authors.forename: Amanda G
authors.initials: AG
authors.lastname: Nichols
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke University, Durham, NC 27710, USA; Department of Immunology, Duke University, Durham, NC 27710, USA; Duke Molecular Physiology Institute, Duke University, Durham, NC 27710, USA.
authors.forename: Sivan
authors.initials: S
authors.lastname: Cohen
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke University, Durham, NC 27710, USA.
authors.forename: Valerie A
authors.initials: VA
authors.lastname: Gerriets
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke University, Durham, NC 27710, USA; Department of Immunology, Duke University, Durham, NC 27710, USA; Duke Molecular Physiology Institute, Duke University, Durham, NC 27710, USA; Department of Pathology, Microbiology, and Immunology, Vanderbilt Center for Immunobiology, Vanderbilt University, Nashville, TN 37232, USA.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Siska
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke University, Durham, NC 27710, USA.
authors.forename: Andrew N
authors.initials: AN
authors.lastname: Macintyre
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke University, Durham, NC 27710, USA.
authors.forename: Pankuri
authors.initials: P
authors.lastname: Goraksha-Hicks
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, Vanderbilt Ingram Cancer Center, Vanderbilt University, Nashville, TN 37232, USA.
authors.forename: Aguirre A
authors.initials: AA
authors.lastname: de Cubas
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke University, Durham, NC 27710, USA.
authors.forename: Tingyu
authors.initials: T
authors.lastname: Liu
authors.affiliation: Division of Nutritional Sciences, Cornell University, Ithaca, NY 14853, USA.
authors.forename: Marc O
authors.initials: MO
authors.lastname: Warmoes
authors.affiliation: Department of Medicine, University of Iowa, Iowa City, IA 52242, USA.
authors.forename: E Dale
authors.initials: ED
authors.lastname: Abel
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, Singapore 119077, Singapore; Department of Pediatrics, National University Health System, Singapore 119228, Singapore.
authors.forename: Allen Eng Juh
authors.initials: AE
authors.lastname: Yeoh
authors.affiliation: UNC Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7295, USA.
authors.forename: Timothy R
authors.initials: TR
authors.lastname: Gershon
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, Vanderbilt Ingram Cancer Center, Vanderbilt University, Nashville, TN 37232, USA.
authors.forename: W Kimryn
authors.initials: WK
authors.lastname: Rathmell
authors.affiliation: UNC Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7295, USA.
authors.forename: Kristy L
authors.initials: KL
authors.lastname: Richards
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke University, Durham, NC 27710, USA; Division of Nutritional Sciences, Cornell University, Ithaca, NY 14853, USA.
authors.forename: Jason W
authors.initials: JW
authors.lastname: Locasale
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke University, Durham, NC 27710, USA; Department of Immunology, Duke University, Durham, NC 27710, USA; Duke Molecular Physiology Institute, Duke University, Durham, NC 27710, USA; Department of Pathology, Microbiology, and Immunology, Vanderbilt Center for Immunobiology, Vanderbilt University, Nashville, TN 37232, USA. Electronic address: jeff.rathmell@vanderbilt.edu.
authors.forename: Jeffrey C
authors.initials: JC
authors.lastname: Rathmell
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000818:Animals; D045744:Cell Line, Tumor; D002470:Cell Survival; D006019:Glycolysis; D006801:Humans; D000076222:Mechanistic Target of Rapamycin Complex 1; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000378:metabolism* / Q000473:pathology; D046912:Multiprotein Complexes / Q000378:metabolism; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000378:metabolism* / Q000473:pathology; D051880:Receptors, Notch / Q000378:metabolism; D015398:Signal Transduction; D013312:Stress, Physiological; D013601:T-Lymphocytes / Q000378:metabolism / Q000473:pathology; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: D046912:Multiprotein Complexes; D051880:Receptors, Notch; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases