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Inhibition of mitochondrial folate metabolism drives differentiation through mTORC1 mediated purine sensing

Author

Listed:
  • Martha M. Zarou

    (University of Glasgow)

  • Kevin M. Rattigan

    (University of Glasgow)

  • Daniele Sarnello

    (University of Glasgow)

  • Engy Shokry

    (Cancer Research UK Scotland Institute)

  • Amy Dawson

    (University of Glasgow)

  • Angela Ianniciello

    (University of Glasgow)

  • Karen Dunn

    (University of Glasgow)

  • Mhairi Copland

    (University of Glasgow)

  • David Sumpton

    (Cancer Research UK Scotland Institute)

  • Alexei Vazquez

    (University of Glasgow)

  • G. Vignir Helgason

    (University of Glasgow)

Abstract

Supporting cell proliferation through nucleotide biosynthesis is an essential requirement for cancer cells. Hence, inhibition of folate-mediated one carbon (1C) metabolism, which is required for nucleotide synthesis, has been successfully exploited in anti-cancer therapy. Here, we reveal that mitochondrial folate metabolism is upregulated in patient-derived leukaemic stem cells (LSCs). We demonstrate that inhibition of mitochondrial 1C metabolism through impairment of de novo purine synthesis has a cytostatic effect on chronic myeloid leukaemia (CML) cells. Consequently, changes in purine nucleotide levels lead to activation of AMPK signalling and suppression of mTORC1 activity. Notably, suppression of mitochondrial 1C metabolism increases expression of erythroid differentiation markers. Moreover, we find that increased differentiation occurs independently of AMPK signalling and can be reversed through reconstitution of purine levels and reactivation of mTORC1. Of clinical relevance, we identify that combination of 1C metabolism inhibition with imatinib, a frontline treatment for CML patients, decreases the number of therapy-resistant CML LSCs in a patient-derived xenograft model. Our results highlight a role for folate metabolism and purine sensing in stem cell fate decisions and leukaemogenesis.

Suggested Citation

  • Martha M. Zarou & Kevin M. Rattigan & Daniele Sarnello & Engy Shokry & Amy Dawson & Angela Ianniciello & Karen Dunn & Mhairi Copland & David Sumpton & Alexei Vazquez & G. Vignir Helgason, 2024. "Inhibition of mitochondrial folate metabolism drives differentiation through mTORC1 mediated purine sensing," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-46114-0
    DOI: 10.1038/s41467-024-46114-0
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    References listed on IDEAS

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    1. Roland Nilsson & Mohit Jain & Nikhil Madhusudhan & Nina Gustafsson Sheppard & Laura Strittmatter & Caroline Kampf & Jenny Huang & Anna Asplund & Vamsi K. Mootha, 2014. "Metabolic enzyme expression highlights a key role for MTHFD2 and the mitochondrial folate pathway in cancer," Nature Communications, Nature, vol. 5(1), pages 1-10, May.
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