1. AMPK/FIS1-Mediated Mitophagy Is Required for Self-Renewal of Human AML Stem Cells
- Author
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Pei, Shanshan, Minhajuddin, Mohammad, Adane, Biniam, Khan, Nabilah, Stevens, Brett M, Mack, Stephen C, Lai, Sisi, Rich, Jeremy N, Inguva, Anagha, Shannon, Kevin M, Kim, Hyunmin, Tan, Aik-Choon, Myers, Jason R, Ashton, John M, Neff, Tobias, Pollyea, Daniel A, Smith, Clayton A, and Jordan, Craig T
- Subjects
Biochemistry and Cell Biology ,Biological Sciences ,Cancer ,Rare Diseases ,Stem Cell Research - Nonembryonic - Human ,Stem Cell Research ,Hematology ,Stem Cell Research - Nonembryonic - Non-Human ,Aetiology ,2.1 Biological and endogenous factors ,1.1 Normal biological development and functioning ,Underpinning research ,Generic health relevance ,AMP-Activated Protein Kinases ,Animals ,Cell Self Renewal ,Cells ,Cultured ,Female ,Humans ,Leukemia ,Myeloid ,Acute ,Membrane Proteins ,Mice ,Mice ,Inbred NOD ,Mice ,Transgenic ,Mitochondrial Proteins ,Mitophagy ,Neoplastic Stem Cells ,Protein Kinase Inhibitors ,Signal Transduction ,AMPK ,FIS1 ,GSK3 ,acute myeloid leukemia ,differentiation ,leukemia stem cells ,mitochondrial dynamics ,mitophagy ,Medical and Health Sciences ,Developmental Biology ,Biological sciences ,Biomedical and clinical sciences - Abstract
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.
- Published
- 2018