2. Academic Validation
  3. Disrupting Mitochondrial Copper Distribution Inhibits Leukemic Stem Cell Self-Renewal

Disrupting Mitochondrial Copper Distribution Inhibits Leukemic Stem Cell Self-Renewal

  • Cell Stem Cell. 2020 Jun 4;26(6):926-937.e10. doi: 10.1016/j.stem.2020.04.010.
Rashim Pal Singh 1,  Danny V Jeyaraju 1,  Veronique Voisin 2,  Rose Hurren 1,  Changjiang Xu 2,  James R Hawley 1,  Samir H Barghout 1,  Dilshad H Khan 1,  Marcela Gronda 1,  Xiaoming Wang 1,  Yulia Jitkova 1,  David Sharon 1,  Sanduni Liyanagae 1,  Neil MacLean 1,  Ayesh K Seneviratene 1,  Sara Mirali 1,  Adina Borenstein 1,  Geethu E Thomas 1,  Joelle Soriano 1,  Elias Orouji 1,  Mark D Minden 1,  Andrea Arruda 1,  Steven M Chan 1,  Gary D Bader 2,  Mathieu Lupien 1,  Aaron D Schimmer 3
Affiliations

Affiliations

  • 1 Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
  • 2 The Donnelly Centre, University of Toronto, Toronto, ON, Canada.
  • 3 Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada. Electronic address: aaron.schimmer@uhn.ca.
PMID: 32416059 DOI: 10.1016/j.stem.2020.04.010
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.

Keywords

ALR; AML; COX17; LSCs; copper.

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