AMPK/FIS1-Mediated Mitophagy Is Required for Self-Renewal of Human AML Stem Cells.
Cell Stem Cell
; 23(1): 86-100.e6, 2018 Jul 05.
Article
em En
| MEDLINE
| ID: mdl-29910151
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.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Células-Tronco Neoplásicas
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Leucemia Mieloide Aguda
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Proteínas Mitocondriais
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Proteínas Quinases Ativadas por AMP
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Mitofagia
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Autorrenovação Celular
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Proteínas de Membrana
Limite:
Animals
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Female
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Humans
Idioma:
En
Revista:
Cell Stem Cell
Ano de publicação:
2018
Tipo de documento:
Article
País de afiliação:
Estados Unidos