New Collaborative Publication from Multiple MBP Scientists

May 20, 2020

Graphical AbstractGraphical Abstract

Multiple MBP scientists have contributed to a new Cell Stem Cell article entitled 'Disrupting Mitochondrial Copper Distribution Inhibits Leukemic Stem Cell Self-Renewal'. The paper includes contributions from several MBP faculty members, including Dr. Steven Chan, Dr. Mathieu Lupien, Dr. Mark Minden  and Dr. Aaron Schimmer.

Article Abstract
"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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View full article on the Cell website.