1. AMPK/FIS1-Mediated Mitophagy Is Required for Self-Renewal of Human AML Stem Cells
- Author
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Brett M. Stevens, Daniel A. Pollyea, Shanshan Pei, Jason R. Myers, Anagha Inguva, Craig T. Jordan, John M. Ashton, Tobias Neff, Stephen C. Mack, Clayton A. Smith, Hyunmin Kim, Kevin Shannon, Nabilah Khan, Jeremy N. Rich, Mohammad Minhajuddin, Aik Choon Tan, Sisi Lai, and Biniam Adane
- Subjects
0301 basic medicine ,Myeloid ,AMPK ,Regulator ,AMP-Activated Protein Kinases ,Medical and Health Sciences ,Transgenic ,GSK3 ,Mice ,Mice, Inbred NOD ,Stem Cell Research - Nonembryonic - Human ,Mitophagy ,2.1 Biological and endogenous factors ,Cell Self Renewal ,Aetiology ,Cells, Cultured ,Cancer ,Cultured ,Leukemia ,Myeloid leukemia ,Cell Differentiation ,differentiation ,leukemia stem cells ,Hematology ,Biological Sciences ,Cell biology ,Leukemia, Myeloid, Acute ,medicine.anatomical_structure ,Neoplastic Stem Cells ,Molecular Medicine ,FIS1 ,Female ,Stem Cell Research - Nonembryonic - Non-Human ,Stem cell ,Signal Transduction ,endocrine system ,Cells ,1.1 Normal biological development and functioning ,Mice, Transgenic ,Biology ,Acute ,acute myeloid leukemia ,Article ,Mitochondrial Proteins ,03 medical and health sciences ,Rare Diseases ,Underpinning research ,Genetics ,medicine ,Animals ,Humans ,Protein Kinase Inhibitors ,Membrane Proteins ,Cell Biology ,medicine.disease ,Stem Cell Research ,mitochondrial dynamics ,030104 developmental biology ,Inbred NOD ,Generic health relevance ,Developmental Biology - 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