PMID- 32416059
OWN - NLM
STAT- MEDLINE
DCOM- 20210427
LR  - 20210427
IS  - 1875-9777 (Electronic)
IS  - 1875-9777 (Linking)
VI  - 26
IP  - 6
DP  - 2020 Jun 4
TI  - Disrupting Mitochondrial Copper Distribution Inhibits Leukemic Stem Cell 
      Self-Renewal.
PG  - 926-937.e10
LID - S1934-5909(20)30149-1 [pii]
LID - 10.1016/j.stem.2020.04.010 [doi]
AB  - 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.
CI  - Copyright (c) 2020 Elsevier Inc. All rights reserved.
FAU - Singh, Rashim Pal
AU  - Singh RP
AD  - Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
FAU - Jeyaraju, Danny V
AU  - Jeyaraju DV
AD  - Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
FAU - Voisin, Veronique
AU  - Voisin V
AD  - The Donnelly Centre, University of Toronto, Toronto, ON, Canada.
FAU - Hurren, Rose
AU  - Hurren R
AD  - Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
FAU - Xu, Changjiang
AU  - Xu C
AD  - The Donnelly Centre, University of Toronto, Toronto, ON, Canada.
FAU - Hawley, James R
AU  - Hawley JR
AD  - Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
FAU - Barghout, Samir H
AU  - Barghout SH
AD  - Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
FAU - Khan, Dilshad H
AU  - Khan DH
AD  - Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
FAU - Gronda, Marcela
AU  - Gronda M
AD  - Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
FAU - Wang, Xiaoming
AU  - Wang X
AD  - Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
FAU - Jitkova, Yulia
AU  - Jitkova Y
AD  - Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
FAU - Sharon, David
AU  - Sharon D
AD  - Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
FAU - Liyanagae, Sanduni
AU  - Liyanagae S
AD  - Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
FAU - MacLean, Neil
AU  - MacLean N
AD  - Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
FAU - Seneviratene, Ayesh K
AU  - Seneviratene AK
AD  - Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
FAU - Mirali, Sara
AU  - Mirali S
AD  - Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
FAU - Borenstein, Adina
AU  - Borenstein A
AD  - Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
FAU - Thomas, Geethu E
AU  - Thomas GE
AD  - Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
FAU - Soriano, Joelle
AU  - Soriano J
AD  - Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
FAU - Orouji, Elias
AU  - Orouji E
AD  - Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
FAU - Minden, Mark D
AU  - Minden MD
AD  - Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
FAU - Arruda, Andrea
AU  - Arruda A
AD  - Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
FAU - Chan, Steven M
AU  - Chan SM
AD  - Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
FAU - Bader, Gary D
AU  - Bader GD
AD  - The Donnelly Centre, University of Toronto, Toronto, ON, Canada.
FAU - Lupien, Mathieu
AU  - Lupien M
AD  - Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
FAU - Schimmer, Aaron D
AU  - Schimmer AD
AD  - Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada. 
      Electronic address: aaron.schimmer@uhn.ca.
LA  - eng
GR  - CIHR/Canada
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20200515
PL  - United States
TA  - Cell Stem Cell
JT  - Cell stem cell
JID - 101311472
RN  - 789U1901C5 (Copper)
SB  - IM
MH  - Cell Differentiation
MH  - *Cell Self Renewal
MH  - Copper
MH  - Humans
MH  - *Leukemia, Myeloid, Acute
MH  - Neoplastic Stem Cells
OTO - NOTNLM
OT  - ALR
OT  - AML
OT  - COX17
OT  - LSCs
OT  - copper
COIS- 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.
EDAT- 2020/05/18 06:00
MHDA- 2021/04/28 06:00
CRDT- 2020/05/17 06:00
PHST- 2019/05/03 00:00 [received]
PHST- 2020/02/27 00:00 [revised]
PHST- 2020/04/15 00:00 [accepted]
PHST- 2020/05/18 06:00 [pubmed]
PHST- 2021/04/28 06:00 [medline]
PHST- 2020/05/17 06:00 [entrez]
AID - S1934-5909(20)30149-1 [pii]
AID - 10.1016/j.stem.2020.04.010 [doi]
PST - ppublish
SO  - Cell Stem Cell. 2020 Jun 4;26(6):926-937.e10. doi: 10.1016/j.stem.2020.04.010. 
      Epub 2020 May 15.