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| Status |
Public on Apr 14, 2020 |
| Title |
Disrupting mitochondrial copper distribution inhibits leukemic stem cell self-renewal |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by high throughput sequencing
Methylation profiling by high throughput sequencing
Genome binding/occupancy profiling by high throughput sequencing
|
| Summary |
Leukemic stem cells (LSC) rely on oxidative metabolism and are differentially sensitive to targeting mitochondrial pathways, which spares normal hematopoietic cells. A subset of mitochondrial proteins are 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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| Overall design |
ATAC seq(3+3+2 replicates), Next Gen RNA seq (3+3+3 replicates) and Cap meth seq (3+3+2 replicates) on OCI-AML2 cells after treatment with ALR (GFER) inhibitor MitoBloCK-6 with or without copper chelator penicillamine.
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| Contributor(s) |
Singh RP, Voisin V, Hawley JR, Bader GD, Lupien M, Schimmer AD |
| Citation(s) |
32416059 |
| |
| Submission date |
Mar 02, 2020 |
| Last update date |
May 25, 2020 |
| Contact name |
Rashim Pal Singh |
| E-mail(s) |
rashimpal@gmail.com
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| Organization name |
Princess Margaret Cancer Centre, UHN
|
| Street address |
101, College Street
|
| City |
Toronto |
| ZIP/Postal code |
M5G 1L7 |
| Country |
Canada |
| |
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| Platforms (2) |
| GPL18573 |
Illumina NextSeq 500 (Homo sapiens) |
| GPL24676 |
Illumina NovaSeq 6000 (Homo sapiens) |
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| Samples (25)
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| Relations |
| BioProject |
PRJNA609914 |
| SRA |
SRP251358 |
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