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.

    On June 11, a study published AMPK/FIS1-Mediated Mitophagy Is Required for Self-Renewal of Human AML Stem Cells in cell stem cell showed that Human AML LSCs display high FIS1 expression and unique mitochondrial morphology.

    Human LSC relies on FIS1-mediated mitochondrial autophagy to achieve self-renewal and survival.AMPK is constitutively active in human LSCs, located upstream of FIS1, regulating FIS1 expression, and stimulating mitochondrial autophagy.Destruction of AMPK signaling or FIS1 activity leads to eradication of LSC, which reduces mitochondrial autophagy and impairs the LSC potential of AML. FIS1 loss induces cell differentiation,cell cycle arrest,GSK3 inhibition in AML.

    In AML, mitochondrial translation, mitochondrial DNA copy number, and other properties have been shown to differ from normal hematopoietic cells, suggesting that altering mitochondrial activity plays an important role in leukemia production. In the study, the LSCs of AML are in a unique state of mitochondrial dynamics mediated by AMPK and FIS1 activation, which mediates downstream signaling through GSK3. The data show that AMPK can regulate FIS1 at the gene and protein levels, but it is unclear whether the association between AMKP and FIS1 is direct. AMPK signaling is active in LSCs with low ROS, and inhibition of AMPK leads to loss of LSC potential. It is suggested that AMPK signaling may be a direct node of cell or mitochondrial stress and FIS1-mediated mitochondrial autophagy.

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