PMID- 34120146 OWN - NLM STAT- MEDLINE DCOM- 20211229 LR - 20221027 IS - 1476-5551 (Electronic) IS - 0887-6924 (Print) IS - 0887-6924 (Linking) VI - 35 IP - 12 DP - 2021 Dec TI - Metabolic alterations mediated by STAT3 promotes drug persistence in CML. PG - 3371-3382 LID - 10.1038/s41375-021-01315-0 [doi] AB - 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. CI - (c) 2021. The Author(s). FAU - Patel, Sweta B AU - Patel SB AUID- ORCID: 0000-0001-7082-7204 AD - Department of Medicine, Division of Hematology/Oncology, O'Neal Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL, USA. FAU - Nemkov, Travis AU - Nemkov T AUID- ORCID: 0000-0001-8566-7119 AD - Department of Biochemistry and Molecular Genetics, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA. FAU - Stefanoni, Davide AU - Stefanoni D AD - Department of Biochemistry and Molecular Genetics, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA. FAU - Benavides, Gloria A AU - Benavides GA AD - Department of Pathology, Center for Free Radical Biology, University of Alabama at Birmingham, Birmingham, AL, USA. FAU - Bassal, Mahmoud A AU - Bassal MA AUID- ORCID: 0000-0003-4322-2968 AD - Department of Systems Biology, Harvard Medical School, Boston, MA, USA. AD - Cancer Institute of Singapore, National University of Singapore, Singapore, Singapore. FAU - Crown, Brittany L AU - Crown BL AD - Department of Medicine, Division of Hematology/Oncology, O'Neal Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL, USA. FAU - Matkins, Victoria R AU - Matkins VR AD - Department of Medicine, Division of Hematology/Oncology, O'Neal Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL, USA. FAU - Camacho, Virginia AU - Camacho V AD - Department of Medicine, Division of Hematology/Oncology, O'Neal Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL, USA. FAU - Kuznetsova, Valeriya AU - Kuznetsova V AD - Department of Medicine, Division of Hematology/Oncology, O'Neal Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL, USA. FAU - Hoang, Ashley T AU - Hoang AT AD - Department of Medicine, Division of Hematology/Oncology, O'Neal Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL, USA. FAU - Tenen, Danielle E AU - Tenen DE AD - Division of Endocrinology, Beth Israel Deaconess Medical Center, Boston, MA, USA. FAU - Wolock, Samuel L AU - Wolock SL AD - Division of Endocrinology, Beth Israel Deaconess Medical Center, Boston, MA, USA. FAU - Park, Jihye AU - Park J AD - Dicerna Pharmaceuticals, Inc., Lexington, MA, USA. FAU - Ying, Li AU - Ying L AD - Cancer Institute of Singapore, National University of Singapore, Singapore, Singapore. FAU - Yue, Zongliang AU - Yue Z AD - Informatics Institute, School of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA. FAU - Chen, Jake Y AU - Chen JY AUID- ORCID: 0000-0001-8829-7504 AD - Informatics Institute, School of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA. FAU - Yang, Henry AU - Yang H AD - Cancer Institute of Singapore, National University of Singapore, Singapore, Singapore. FAU - Tenen, Daniel G AU - Tenen DG AUID- ORCID: 0000-0002-6423-3888 AD - Cancer Institute of Singapore, National University of Singapore, Singapore, Singapore. FAU - Ferrell, Paul Brent AU - Ferrell PB AUID- ORCID: 0000-0003-1140-9154 AD - Division of Hematology/Oncology, Vanderbilt University Medical Center, Nashville, TN, USA. FAU - Lu, Rui AU - Lu R AD - Department of Medicine, Division of Hematology/Oncology, O'Neal Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL, USA. FAU - Darley-Usmar, Victor AU - Darley-Usmar V AD - Department of Pathology, Center for Free Radical Biology, University of Alabama at Birmingham, Birmingham, AL, USA. FAU - D'Alessandro, Angelo AU - D'Alessandro A AD - Department of Biochemistry and Molecular Genetics, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA. FAU - Bhatia, Ravi AU - Bhatia R AUID- ORCID: 0000-0001-5740-2316 AD - Department of Medicine, Division of Hematology/Oncology, O'Neal Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL, USA. FAU - Welner, Robert S AU - Welner RS AUID- ORCID: 0000-0003-2498-9469 AD - Department of Medicine, Division of Hematology/Oncology, O'Neal Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL, USA. rwelner@uab.edu. LA - eng GR - P30 AI027767/AI/NIAID NIH HHS/United States GR - P30 CA013148/CA/NCI NIH HHS/United States GR - P01 HL131477/HL/NHLBI NIH HHS/United States GR - R35 CA197697/CA/NCI NIH HHS/United States GR - R01 CA095684/CA/NCI NIH HHS/United States GR - K23 HL138291/HL/NHLBI NIH HHS/United States GR - R01 CA248794/CA/NCI NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20210612 PL - England TA - Leukemia JT - Leukemia JID - 8704895 RN - 0 (Protein Kinase Inhibitors) RN - 0 (STAT3 Transcription Factor) RN - 0 (Small Molecule Libraries) RN - 0 (Stat3 protein, mouse) SB - IM MH - Animals MH - Apoptosis MH - *Drug Resistance, Neoplasm MH - Female MH - Glycolysis MH - Leukemia, Myelogenous, Chronic, BCR-ABL Positive/*drug therapy/genetics/metabolism/pathology MH - Male MH - *Metabolome MH - Mice MH - Neoplastic Stem Cells/*drug effects/metabolism/pathology MH - Protein Kinase Inhibitors/pharmacology MH - STAT3 Transcription Factor/genetics/*metabolism MH - Small Molecule Libraries/*pharmacology MH - *Transcriptome PMC - PMC8632690 MID - NIHMS1716989 COIS- None of the material has been published or is under consideration for publication elsewhere. The authors have no financial conflicts of interest that might influence our results or their interpretation, and all authors have reviewed and agree to submit this manuscript. EDAT- 2021/06/14 06:00 MHDA- 2021/12/30 06:00 PMCR- 2021/06/12 CRDT- 2021/06/13 21:01 PHST- 2020/11/04 00:00 [received] PHST- 2021/05/28 00:00 [accepted] PHST- 2021/05/16 00:00 [revised] PHST- 2021/06/14 06:00 [pubmed] PHST- 2021/12/30 06:00 [medline] PHST- 2021/06/13 21:01 [entrez] PHST- 2021/06/12 00:00 [pmc-release] AID - 10.1038/s41375-021-01315-0 [pii] AID - 1315 [pii] AID - 10.1038/s41375-021-01315-0 [doi] PST - ppublish SO - Leukemia. 2021 Dec;35(12):3371-3382. doi: 10.1038/s41375-021-01315-0. Epub 2021 Jun 12.