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.

中文翻译：

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AMPK / FIS1介导的线粒体是人类AML干细胞自我更新所必需的。

白血病干细胞（LSC）被认为可驱动急性髓细胞性白血病（AML）的发生以及化疗后的复发。由于其独特的生物学特性，开发有效的方法来根除LSC一直是一项重大挑战。在本研究中，我们证明线粒体动力学调节剂FIS1的固有过表达介导了对原始AML细胞必不可少的线粒体活性。FIS1的耗竭会削弱线粒体并导致GSK3失活，髓样分化，细胞周期停滞以及LSC自我更新潜能的极大丧失。此外，我们报告中央代谢应激调节剂AMPK在LSC人群中也被内在激活，并且位于FIS1的上游。抑制AMPK信号概括了FIS1丢失的生物学效应。