Metabolic alterations mediated by STAT3 promotes drug persistence in CML
| العنوان: | Metabolic alterations mediated by STAT3 promotes drug persistence in CML |
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| المؤلفون: | Sweta B. Patel, Jake Y. Chen, Zongliang Yue, Victor M. Darley-Usmar, Brittany L. Crown, Ravi Bhatia, Daniel G. Tenen, Rui Lu, Li Ying, Paul Brent Ferrell, Davide Stefanoni, Ashley T. Hoang, Samuel L. Wolock, Danielle Tenen, Travis Nemkov, Angelo D'Alessandro, Robert S. Welner, Jihye Park, Henry Yang, Valeriya Kuznetsova, Gloria A. Benavides, Mahmoud A. Bassal, Virginia Camacho, Victoria R. Matkins |
| المصدر: | Leukemia |
| بيانات النشر: | Springer Science and Business Media LLC, 2021. |
| سنة النشر: | 2021 |
| مصطلحات موضوعية: | Male, STAT3 Transcription Factor, 0301 basic medicine, Cancer Research, medicine.drug_class, Apoptosis, Biology, Article, Tyrosine-kinase inhibitor, Small Molecule Libraries, Transcriptome, Mice, 03 medical and health sciences, 0302 clinical medicine, Leukemia, Myelogenous, Chronic, BCR-ABL Positive, hemic and lymphatic diseases, medicine, Animals, Glycolysis, Progenitor cell, STAT3, Protein Kinase Inhibitors, Transcription factor, Myeloid leukemia, Hematology, respiratory tract diseases, 030104 developmental biology, Oncology, Drug Resistance, Neoplasm, 030220 oncology & carcinogenesis, Metabolome, Neoplastic Stem Cells, Cancer research, biology.protein, Female, Stem cell |
| الوصف: | 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. |
| تدمد: | 1476-5551 0887-6924 |
| DOI: | 10.1038/s41375-021-01315-0 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::0f73c6ca4abbc6e8ae6be675a382c70d https://doi.org/10.1038/s41375-021-01315-0 |
| Rights: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....0f73c6ca4abbc6e8ae6be675a382c70d |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 14765551 08876924 |
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| DOI: | 10.1038/s41375-021-01315-0 |