4.7 Article

AMPK/FIS1-Mediated Mitophagy Is Required for Self-Renewal of Human AML Stem Cells

期刊

CELL STEM CELL
卷 23, 期 1, 页码 86-+

出版社

CELL PRESS
DOI: 10.1016/j.stem.2018.05.021

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资金

  1. Nancy Carroll Allen Chair in Hematology Research
  2. NIH [R01CA200707, R01CA16626505S1, F31CA196330-01, R01CA193994]
  3. University of Colorado Department of Medicine Outstanding Early Career Scholar Program
  4. University of Colorado Cancer Center [P30CA046934]
  5. Bioinformatics Core
  6. NIH MSTP [T32 GM008497]
  7. University of Colorado Cancer Center Development Therapeutics Pilot Grant Award
  8. NIH/NCATS Colorado CTSI grant [UL1 TR001082]
  9. NATIONAL CANCER INSTITUTE [F31CA196330, R01CA200707, P30CA046934, R01CA193994, R01CA166265] Funding Source: NIH RePORTER
  10. NATIONAL CENTER FOR ADVANCING TRANSLATIONAL SCIENCES [UL1TR001082, UL1TR002535] Funding Source: NIH RePORTER
  11. NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES [P30DK048520] Funding Source: NIH RePORTER
  12. NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [T32GM008497] Funding Source: NIH RePORTER

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Leukemia stem cells (LSCs) are thought to drive the genesis of acute myeloid leukemia (AML) as well as relapse following chemotherapy. Because of their unique biology, developing effective methods to eradicate LSCs has been a significant challenge. In the present study, we demonstrate that intrinsic overexpression of the mitochondrial dynamics regulator FIS1 mediates mitophagy activity that is essential for primitive AML cells. Depletion of FIS1 attenuates mitophagy and leads to inactivation of GSK3, myeloid differentiation, cell cycle arrest, and a profound loss of LSC self-renewal potential. Further, we report that the central metabolic stress regulator AMPK is also intrinsically activated in LSC populations and is upstream of FIS1. Inhibition of AMPK signaling recapitulates the biological effect of FIS1 loss. These data suggest a model in which LSCs co-opt AMPK/FIS1-mediated mitophagy as a means to maintain stem cell properties that may be otherwise compromised by the stresses induced by oncogenic transformation.

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