AMPK Is Essential to Balance Glycolysis and Mitochondrial Metabolism to Control T-ALL Cell Stress and Survival.
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.
Duke Scholars
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Related Subject Headings
- TOR Serine-Threonine Kinases
- T-Lymphocytes
- Stress, Physiological
- Signal Transduction
- Receptors, Notch
- Precursor Cell Lymphoblastic Leukemia-Lymphoma
- Multiprotein Complexes
- Mitochondria
- Mice, Inbred C57BL
- Mechanistic Target of Rapamycin Complex 1
Citation
Published In
DOI
EISSN
Publication Date
Volume
Issue
Start / End Page
Location
Related Subject Headings
- TOR Serine-Threonine Kinases
- T-Lymphocytes
- Stress, Physiological
- Signal Transduction
- Receptors, Notch
- Precursor Cell Lymphoblastic Leukemia-Lymphoma
- Multiprotein Complexes
- Mitochondria
- Mice, Inbred C57BL
- Mechanistic Target of Rapamycin Complex 1