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Title: Metabolic alterations mediated by STAT3 promotes drug persistence in CML
Authors: Patel, Sweta B.
Nemkov, Travis
Stefanoni, Davide
Benavides, Gloria A.
Bassal, Mahmoud A. 
Crown, Brittany L.
Matkins, Victoria R.
Camacho, Virginia
Kuznetsova, Valeriya
Hoang, Ashley T.
Tenen, Danielle E.
Wolock, Samuel L.
Park, Jihye
Ying, Li 
Yue, Zongliang
Chen, Jake Y.
Yang, Henry 
Tenen, Daniel G. 
Ferrell, Paul Brent
Lu, Rui
Darley-Usmar, Victor
D’Alessandro, A.
Bhatia, Ravi
Welner, Robert S.
Issue Date: 12-Jun-2021
Publisher: Springer Nature
Citation: Patel, Sweta B., Nemkov, Travis, Stefanoni, Davide, Benavides, Gloria A., Bassal, Mahmoud A., Crown, Brittany L., Matkins, Victoria R., Camacho, Virginia, Kuznetsova, Valeriya, Hoang, Ashley T., Tenen, Danielle E., Wolock, Samuel L., Park, Jihye, Ying, Li, Yue, Zongliang, Chen, Jake Y., Yang, Henry, Tenen, Daniel G., Ferrell, Paul Brent, Lu, Rui, Darley-Usmar, Victor, D’Alessandro, A., Bhatia, Ravi, Welner, Robert S. (2021-06-12). Metabolic alterations mediated by STAT3 promotes drug persistence in CML. Leukemia 35 (12) : 3371-3382. ScholarBank@NUS Repository.
Rights: Attribution 4.0 International
Abstract: 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. © 2021, The Author(s).
Source Title: Leukemia
ISSN: 0887-6924
DOI: 10.1038/s41375-021-01315-0
Rights: Attribution 4.0 International
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