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

Martha M. Zarou, Kevin M. Rattigan, Daniele Sarnello, Engy Shokry, Amy Dawson, Angela Ianniciello, Karen Dunn, Mhairi Copland, David Sumpton, Alexei Vazquez () and G. Vignir Helgason ()
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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

Nature Communications, 2024, vol. 15, issue 1, 1-18

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-46114-0

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