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Series GSE165405 Query DataSets for GSE165405
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.
Overall design RNAseq analysis of DND41 cells after treatment with DMSO or MB1-47.
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
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
Platforms (1)
GPL24676 Illumina NovaSeq 6000 (Homo sapiens)
Samples (6)
GSM5032895 MB1_1
GSM5032896 MB1_2
GSM5032897 MB1_3
BioProject PRJNA694438
SRA SRP303033

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Supplementary file Size Download File type/resource
GSE165405_DND41_MB1_vs_Control_DESeqNormalizedCounts.csv.gz 865.0 Kb (ftp)(http) CSV
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Raw data are available in SRA
Processed data are available on Series record

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