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

Cell Stem Cell. 2018 Jul 05;23(1):86-100.e6. Epub 2018 Jun 14
Shanshan Pei 1 , Mohammad Minhajuddin 1 , Biniam Adane 1 , Nabilah Khan 1 , Brett M Stevens 1 , Stephen C Mack 2 , Sisi Lai 2 , Jeremy N Rich 2 , Anagha Inguva 1 , Kevin M Shannon 3 , Hyunmin Kim 4 , Aik-Choon Tan 4 , Jason R Myers 5 , John M Ashton 5 , Tobias Neff 6 , Daniel A Pollyea 1 , Clayton A Smith 1 , Craig T Jordan 7
Shanshan Pei 1 , Mohammad Minhajuddin 1 , Biniam Adane 1 , Nabilah Khan 1 , Brett M Stevens 1 , Stephen C Mack 2 , Sisi Lai 2 , Jeremy N Rich 2 , Anagha Inguva 1 , Kevin M Shannon 3 , Hyunmin Kim 4 , Aik-Choon Tan 4 , Jason R Myers 5 , John M Ashton 5 , Tobias Neff 6 , Daniel A Pollyea 1 , Clayton A Smith 1 , Craig T Jordan 7
+ et al

[No authors listed]

Author information
  • 1 Division of Hematology, University of Colorado, Aurora, CO 80045, USA.
  • 2 Department of Stem Cell Biology and Regenerative Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA.
  • 3 Department of Pediatrics, University of California - San Francisco, San Francisco, CA 94143, USA.
  • 4 Division of Medical Oncology, Department of Medicine, University of Colorado, Aurora, CO 80045, USA.
  • 5 Genomics Research Center, University of Rochester, NY 14642, USA.
  • 6 Department of Pediatrics, Section of Pediatric Hematology/Oncology/Bone Marrow Transplantation, University of Colorado Denver, Aurora, CO 80045, USA.
  • 7 Division of Hematology, University of Colorado, Aurora, CO 80045, USA. Electronic address: craig.jordan@ucdenver.edu.

摘要

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.

KEYWORDS: AMPK, FIS1, GSK3, acute myeloid leukemia, differentiation, leukemia stem cells, mitochondrial dynamics, mitophagy

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