Disrupting Mitochondrial Copper Distribution Inhibits Leukemic Stem Cell Self-Renewal

被引：45

作者：

Singh, Rashim Pal ^{[1
]}

Jeyaraju, Danny, V ^{[1
]}

Voisin, Veronique ^{[2
]}

Hurren, Rose ^{[1
]}

Xu, Changjiang ^{[2
]}

Hawley, James R. ^{[1
]}

Barghout, Samir H. ^{[1
]}

Khan, Dilshad H. ^{[1
]}

Gronda, Marcela ^{[1
]}

Wang, Xiaoming ^{[1
]}

Jitkova, Yulia ^{[1
]}

Sharon, David ^{[1
]}

Liyanagae, Sanduni ^{[1
]}

MacLean, Neil ^{[1
]}

Seneviratene, Ayesh K. ^{[1
]}

Mirali, Sara ^{[1
]}

Borenstein, Adina ^{[1
]}

Thomas, Geethu E. ^{[1
]}

Soriano, Joelle ^{[1
]}

Orouji, Elias ^{[1
]}

Minden, Mark D. ^{[1
]}

Arruda, Andrea ^{[1
]}

Chan, Steven M. ^{[1
]}

Bader, Gary D. ^{[2
]}

Lupien, Mathieu ^{[1
]}

Schimmer, Aaron D. ^{[1
]}

机构：

[1] Univ Hlth Network, Princess Margaret Canc Ctr, Toronto, ON, Canada

[2] Univ Toronto, Donnelly Ctr, Toronto, ON, Canada

来源：

CELL STEM CELL | 2020年 / 26卷 / 06期

基金：

加拿大健康研究院;

关键词：

DNA METHYLATION; THERAPEUTIC STRATEGY; READ ALIGNMENT; PROTEIN IMPORT; KEY REGULATOR; METABOLISM; CHAPERONE; TRANSLOCATION; EXPRESSION; CAPACITY;

D O I：

10.1016/j.stem.2020.04.010

中图分类号：

Q813 [细胞工程];

学科分类号：

摘要：

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.

引用

页码：926 / +

页数：22

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