Disrupting Mitochondrial Copper Distribution Inhibits Leukemic Stem Cell Self-Renewal.

Leukemic stem cells (LSCs) rely on oxidative metabolism and are differentially sensitive to targeting mitochondrial pathways, which spares normal hematopoietic cells. A subset of mitochondrial proteins is folded in the intermembrane space via the mitochondrial intermembrane assembly (MIA) pathway. We found increased mRNA expression of MIA pathway substrates in acute myeloid leukemia (AML) stem cells. Therefore, we evaluated the effects of inhibiting this pathway in AML. Genetic and chemical inhibition of ALR reduces AML growth and viability, disrupts LSC self-renewal, and induces their differentiation. ALR inhibition preferentially decreases its substrate COX17, a mitochondrial copper chaperone, and knockdown of COX17 phenocopies ALR loss. Inhibiting ALR and COX17 increases mitochondrial copper levels which in turn inhibit S-adenosylhomocysteine hydrolase (SAHH) and lower levels of S-adenosylmethionine (SAM), DNA methylation, and chromatin accessibility to lower LSC viability. These results provide insight into mechanisms through which mitochondrial copper controls epigenetic status and viability of LSCs.

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Declaration of Interests A.D.S. has received honoraria or consulting fees from Novartis, Jazz, Otsuka, and Takeda Pharmaceuticals and research support from Medivir AB and Takeda. A.D.S. owns stock in Abbvie Pharmaceuticals and is named on a patent application for the use of DNT cells for the treatment of leukemia. D.V.J is currently an employee of Celgene/Bristol-Myers Squibb (BMS). M.D.M. has received consulting fees from Astellas, Abbvie, Celgene/BMS, and GlaxoSmithKline (GSK). S.M.C. has received honoraria from Celgene and Agios. S.M.C. has received research funding from Agios, Celgene, and Abbvie Pharmaceuticals.