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Disrupting Mitochondrial Copper Distribution Inhibits Leukemic Stem Cell Self-Renewal.
Singh, Rashim Pal; Jeyaraju, Danny V; Voisin, Veronique; Hurren, Rose; Xu, Changjiang; Hawley, James R; Barghout, Samir H; Khan, Dilshad H; Gronda, Marcela; Wang, Xiaoming; Jitkova, Yulia; Sharon, David; Liyanagae, Sanduni; MacLean, Neil; Seneviratene, Ayesh K; Mirali, Sara; Borenstein, Adina; Thomas, Geethu E; Soriano, Joelle; Orouji, Elias; Minden, Mark D; Arruda, Andrea; Chan, Steven M; Bader, Gary D; Lupien, Mathieu; Schimmer, Aaron D.
Affiliation
  • Singh RP; Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
  • Jeyaraju DV; Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
  • Voisin V; The Donnelly Centre, University of Toronto, Toronto, ON, Canada.
  • Hurren R; Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
  • Xu C; The Donnelly Centre, University of Toronto, Toronto, ON, Canada.
  • Hawley JR; Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
  • Barghout SH; Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
  • Khan DH; Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
  • Gronda M; Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
  • Wang X; Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
  • Jitkova Y; Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
  • Sharon D; Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
  • Liyanagae S; Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
  • MacLean N; Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
  • Seneviratene AK; Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
  • Mirali S; Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
  • Borenstein A; Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
  • Thomas GE; Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
  • Soriano J; Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
  • Orouji E; Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
  • Minden MD; Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
  • Arruda A; Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
  • Chan SM; Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
  • Bader GD; The Donnelly Centre, University of Toronto, Toronto, ON, Canada.
  • Lupien M; Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
  • Schimmer AD; Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada. Electronic address: aaron.schimmer@uhn.ca.
Cell Stem Cell ; 26(6): 926-937.e10, 2020 06 04.
Article in En | MEDLINE | ID: mdl-32416059
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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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Leukemia, Myeloid, Acute / Cell Self Renewal Limits: Humans Language: En Journal: Cell Stem Cell Year: 2020 Document type: Article Affiliation country: Canadá
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Add to My VHL
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Leukemia, Myeloid, Acute / Cell Self Renewal Limits: Humans Language: En Journal: Cell Stem Cell Year: 2020 Document type: Article Affiliation country: Canadá