W. Rathmell
Last active: 8/8/2016

AMPK Is Essential to Balance Glycolysis and Mitochondrial Metabolism to Control T-ALL Cell Stress and Survival.

Kishton RJ, Barnes CE, Nichols AG, Cohen S, Gerriets VA, Siska PJ, Macintyre AN, Goraksha-Hicks P, de Cubas AA, Liu T, Warmoes MO, Abel ED, Yeoh AE, Gershon TR, Rathmell WK, Richards KL, Locasale JW, Rathmell JC
Cell Metab. 2016 23 (4): 649-62

PMID: 27076078 · PMCID: PMC4832577 · DOI:10.1016/j.cmet.2016.03.008

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.

Copyright © 2016 Elsevier Inc. All rights reserved.

MeSH Terms (16)

AMP-Activated Protein Kinases Animals Cell Line, Tumor Cell Survival Glycolysis Humans Mechanistic Target of Rapamycin Complex 1 Mice, Inbred C57BL Mitochondria Multiprotein Complexes Precursor Cell Lymphoblastic Leukemia-Lymphoma Receptors, Notch Signal Transduction Stress, Physiological T-Lymphocytes TOR Serine-Threonine Kinases

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