Metabolic alterations mediated by STAT3 promotes drug persistence in CML

• Published in: Leukemia 2021-12, Vol.35 (12), p.3371-3382
• Main 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, Angelo, Bhatia, Ravi, Welner, Robert S.
• Format: Article
• Language: English
• Subjects: 38/91; 631/67/1990/283/1896; 631/67/2327; 64/60; 82/58; 82/79; 96/100; 96/106; 96/2; 96/31; Animals; Apoptosis; BCR-ABL protein; Cancer Research; Cell activation; Cell metabolism; Chronic myeloid leukemia; Critical Care Medicine; Drug resistance; Drug Resistance, Neoplasm; Drug therapy; Enzyme inhibitors; Female; Fusion protein; Glycolysis; Health aspects; Hematology; Intensive; Internal Medicine; Leukemia; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - drug therapy; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - genetics; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - metabolism; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - pathology; Male; Medicine; Medicine & Public Health; Metabolic pathways; Metabolism; Metabolome; Metabolomics; Mice; Mitochondria; Myeloid leukemia; Neoplastic Stem Cells - drug effects; Neoplastic Stem Cells - metabolism; Neoplastic Stem Cells - pathology; Oncology; Oxidative phosphorylation; Phosphorylation; Physiological aspects; Progenitor cells; Protein Kinase Inhibitors - pharmacology; Protein-tyrosine kinase; Proteomics; Pyruvate kinase; Pyruvic acid; Small Molecule Libraries - pharmacology; Stat3 protein; STAT3 Transcription Factor - genetics; STAT3 Transcription Factor - metabolism; Stem cells; Transcriptome; Transcriptomics; Tyrosine
• ISSN: 0887-6924; 1476-5551
• DOI: 10.1038/s41375-021-01315-0

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.