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GEO help: Mouse over screen elements for information. |
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| Status |
Public on Jul 06, 2021 |
| Title |
Metabolic alterations mediated by STAT3 promotes drug persistence in CML [ChIP-seq] |
| Organism |
Mus musculus |
| Experiment type |
Genome binding/occupancy profiling by high throughput sequencing
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| Summary |
Leukemic stem cells (LSCs) can acquire non-mutational resistance following drug treatment leading to therapeutic failure and relapse. However, oncogene-independent mechanisms of drug persistence in LSCs are incompletely understood, which is the primary focus of this study. We integrated proteomics, transcriptomics, and metabolomics to determine the contribution of STAT3 in promoting metabolic changes in tyrosine kinase inhibitor (TKI) persistent chronic myeloid leukemia (CML) cells. Proteomic and transcriptional differences in TKI persistent CML cells revealed BCR-ABL-independent STAT3 activation in these cells. While knockout of STAT3 inhibited the CML cells from developing drug-persistence, inhibition of STAT3 using a small molecule inhibitor sensitized the persistent CML cells to TKI treatment. Interestingly, given the role of phosphorylated STAT3 as a transcription factor, it localized uniquely to genes regulating metabolic pathways in the TKI-persistent CML stem and progenitor cells. Subsequently, we observed that STAT3 dysregulated mitochondrial metabolism forcing the TKI-persistent CML cells to depend on glycolysis, unlike TKI-sensitive CML cells, which are more reliant on oxidative phosphorylation. Finally, targeting pyruvate kinase M2, a rate-limiting glycolytic enzyme, specifically eradicated the TKI-persistent CML cells. By exploring the role of STAT3 in altering metabolism, we provide critical insight into identifying potential therapeutic targets for eliminating TKI-persistent LSCs.
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| Overall design |
Comparing drug-sensitive and resistant CML leukemic cells and murine stem progenitor cells
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| Contributor(s) |
Patel SB, Nemkov T, Stefanoni D, Benavides GA, Bassal MA, Crown BL, Matkins VR, Camacho V, Kuznetsova V, Hoang AT, Tenen DE, Wolock SL, Park J, Ying L, Yue Z, JChen JY, Henry Y, Tenen DG, Ferrell PB, Lu R, Darley-Usmar V, D'Alessandro A, Bhatia R, Welner RS |
| Citation(s) |
34120146 |
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| Submission date |
Jun 17, 2020 |
| Last update date |
Jul 07, 2021 |
| Contact name |
Mahmoud Adel Bassal |
| E-mail(s) |
mahmoud.bassal@mymail.unisa.edu.au
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| Organization name |
Beth Israel Deaconess Medical Center
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| Department |
Hematology and Oncology
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| Lab |
Tenen Lab
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| Street address |
3 Blackfan Circle
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| City |
Boston |
| State/province |
Massachusetts |
| ZIP/Postal code |
02131-4834 |
| Country |
USA |
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| Platforms (1) |
| GPL19057 |
Illumina NextSeq 500 (Mus musculus) |
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| Samples (4)
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| This SubSeries is part of SuperSeries: |
| GSE152713 |
Metabolic alterations mediated by STAT3 promotes drug persistence in CML |
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| Relations |
| BioProject |
PRJNA640150 |
| SRA |
SRP267717 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE152701_ChIP_peaks.xlsx |
410.9 Kb |
(ftp)(http) |
XLSX |
| GSE152701_RAW.tar |
704.2 Mb |
(http)(custom) |
TAR (of BW) |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data provided as supplementary file |
| Processed data are available on Series record |
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