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| Status |
Public on Jun 09, 2021 |
| Title |
A novel and highly effective mitochondrial uncoupling drug (MB1-47) in T-cell acute lymphoblastic leukemia |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by high throughput sequencing
|
| Summary |
T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematologic malignancy. Despite recent advances in treatments with intensified chemotherapy regimens, relapse rates and associated morbidities remain high. In this context, metabolic dependencies have emerged as a druggable opportunity for the treatment of leukemia. Here, we tested the antileukemic effects of MB1-47, a newly developed mitochondrial uncoupling compound. MB1-47 treatment in T-ALL cells robustly inhibited cell proliferation via both cytostatic and cytotoxic effects as a result of compromised mitochondrial energy and macromolecule depletion, which severely impair nucleotide biosynthesis. Mechanistically, acute treatment with MB1-47 in primary leukemias promoted AMPK activation and downregulation of mTOR signaling, stalling anabolic pathways that support leukemic cell survival. Indeed, MB1-47 treatment in mice harboring murine NOTCH1-induced leukemias or human T-ALL PDXs led to a potent antileukemic effect with 2-fold extension in survival without overlapping toxicities. Overall, our findings demonstrate a critical role for mitochondrial oxidative phosphorylation in T-ALL and uncover MB1-47-driven mitochondrial uncoupling as a novel therapeutic strategy for the treatment of this disease.
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| Overall design |
RNAseq analysis of DND41 cells after treatment with DMSO or MB1-47.
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| |
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| Contributor(s) |
da Silva-Diz V, Singh A, Khiabanian H, Herranz D |
| Citation(s) |
33876224 |
| |
| Submission date |
Jan 24, 2021 |
| Last update date |
Jun 09, 2021 |
| Contact name |
Daniel Herranz |
| E-mail(s) |
dh710@cinj.rutgers.edu
|
| Organization name |
Rutgers Cancer Institute of New Jersey
|
| Street address |
195 Little Albany Street
|
| City |
New Brunswick |
| State/province |
New Jersey |
| ZIP/Postal code |
08901 |
| Country |
USA |
| |
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| Platforms (1) |
| GPL24676 |
Illumina NovaSeq 6000 (Homo sapiens) |
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| Samples (6)
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| Relations |
| BioProject |
PRJNA694438 |
| SRA |
SRP303033 |
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