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Leukemic stem cells in chronic myeloid leukaemia (CML) exhibit persistent metabolic alterations, specifically increased pyruvate anaplerosis, even after TKI treatment. Targeting this metabolic vulnerability with MPC inhibitors shows promise against imatinib-resistant CML.

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Area of Science:

  • Oncology
  • Metabolic pathways
  • Leukemia stem cell biology

Background:

  • Deregulated oxidative metabolism is characteristic of leukemia.
  • Tyrosine kinase inhibitors (TKIs) improve survival in chronic myeloid leukemia (CML) but do not eliminate leukemic stem cells (LSCs).
  • The metabolic state of TKI-treated CML LSCs remains unclear.

Purpose of the Study:

  • Investigate metabolic adaptations in patient-derived CML LSCs.
  • Determine if TKI treatment affects LSC metabolic deregulation.
  • Identify potential therapeutic targets in CML LSCs.

Main Methods:

  • Multi-omics datasets generation using clinically relevant assays.
  • Stable isotope-assisted metabolomics.
  • Genetic ablation of pyruvate anaplerosis.
  • Pre-clinical CML models using MSDC-0160, an MPC1/2 inhibitor.

Main Results:

  • CML LSCs show increased pyruvate anaplerosis via elevated mitochondrial pyruvate carrier 1/2 (MPC1/2) and pyruvate carboxylase (PC) activity.
  • Imatinib treatment reversed some metabolic reprogramming but did not affect pyruvate anaplerosis.
  • Genetic inhibition of pyruvate anaplerosis sensitized CML cells to imatinib.
  • MSDC-0160 inhibited pyruvate anaplerosis and targeted imatinib-resistant CML LSCs.

Conclusions:

  • Pyruvate anaplerosis is a persistent metabolic vulnerability in CML LSCs, unaffected by imatinib.
  • Targeting pyruvate anaplerosis, particularly with MPC inhibitors like MSDC-0160, offers a potential therapeutic strategy for imatinib-resistant CML.
  • This highlights a novel therapeutic avenue for eradicating residual CML disease.