Metabolic alterations mediated by STAT3 promotes drug persistence in CML

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Sweta B Patel1, Travis Nemkov2, Davide Stefanoni2

  • 1Department of Medicine, Division of Hematology/Oncology, O'Neal Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL, USA.

Leukemia
|June 13, 2021
PubMed

Insights

STAT3 activation drives drug resistance in chronic myeloid leukemia (CML) stem cells by altering metabolism. Targeting STAT3 and its downstream effects, like glycolysis, offers a new strategy to eliminate persistent CML cells.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Leukemic stem cells (LSCs) develop non-mutational drug resistance, causing treatment failure and relapse in chronic myeloid leukemia (CML).
  • Oncogene-independent mechanisms of drug persistence in LSCs remain poorly understood, hindering effective therapeutic strategies.

Purpose of the Study:

  • To investigate the role of STAT3 in metabolic alterations within tyrosine kinase inhibitor (TKI)-persistent CML cells.
  • To identify potential therapeutic targets for eradicating TKI-persistent LSCs.

Main Methods:

  • Integrated analysis of proteomics, transcriptomics, and metabolomics in TKI-persistent CML cells.
  • STAT3 knockout and small molecule inhibition experiments.
  • Investigation of STAT3 localization and its impact on metabolic gene regulation.
  • Analysis of cellular metabolic pathways (glycolysis vs. oxidative phosphorylation).

Main Results:

  • BCR-ABL-independent STAT3 activation was observed in TKI-persistent CML cells.
  • STAT3 inhibition sensitized persistent CML cells to TKI treatment and prevented drug-persistence.
  • STAT3 dysregulated mitochondrial metabolism, shifting TKI-persistent cells towards glycolysis.
  • Targeting pyruvate kinase M2 (PKM2) specifically eradicated TKI-persistent CML cells.

Conclusions:

  • STAT3 plays a critical role in promoting metabolic adaptation and drug resistance in TKI-persistent CML stem and progenitor cells.
  • Targeting STAT3-mediated metabolic reprogramming, particularly glycolysis via enzymes like PKM2, presents a promising therapeutic avenue for overcoming TKI resistance in CML.

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