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

Publication ,  Journal Article
Kishton, RJ; Barnes, CE; Nichols, AG; Cohen, S; Gerriets, VA; Siska, PJ; Macintyre, AN; Goraksha-Hicks, P; de Cubas, AA; Liu, T; Warmoes, MO ...
Published in: Cell Metab
April 12, 2016

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.

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Published In

Cell Metab

DOI

EISSN

1932-7420

Publication Date

April 12, 2016

Volume

23

Issue

4

Start / End Page

649 / 662

Location

United States

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

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Kishton, R. J., Barnes, C. E., Nichols, A. G., Cohen, S., Gerriets, V. A., Siska, P. J., … Rathmell, J. C. (2016). AMPK Is Essential to Balance Glycolysis and Mitochondrial Metabolism to Control T-ALL Cell Stress and Survival. Cell Metab, 23(4), 649–662. https://doi.org/10.1016/j.cmet.2016.03.008
Kishton, Rigel J., Carson E. Barnes, Amanda G. Nichols, Sivan Cohen, Valerie A. Gerriets, Peter J. Siska, Andrew N. Macintyre, et al. “AMPK Is Essential to Balance Glycolysis and Mitochondrial Metabolism to Control T-ALL Cell Stress and Survival.Cell Metab 23, no. 4 (April 12, 2016): 649–62. https://doi.org/10.1016/j.cmet.2016.03.008.
Kishton RJ, Barnes CE, Nichols AG, Cohen S, Gerriets VA, Siska PJ, et al. AMPK Is Essential to Balance Glycolysis and Mitochondrial Metabolism to Control T-ALL Cell Stress and Survival. Cell Metab. 2016 Apr 12;23(4):649–62.
Kishton, Rigel J., et al. “AMPK Is Essential to Balance Glycolysis and Mitochondrial Metabolism to Control T-ALL Cell Stress and Survival.Cell Metab, vol. 23, no. 4, Apr. 2016, pp. 649–62. Pubmed, doi:10.1016/j.cmet.2016.03.008.
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 AEJ, Gershon TR, Rathmell WK, Richards KL, Locasale JW, Rathmell JC. AMPK Is Essential to Balance Glycolysis and Mitochondrial Metabolism to Control T-ALL Cell Stress and Survival. Cell Metab. 2016 Apr 12;23(4):649–662.
Journal cover image

Published In

Cell Metab

DOI

EISSN

1932-7420

Publication Date

April 12, 2016

Volume

23

Issue

4

Start / End Page

649 / 662

Location

United States

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