Zarou, M. M. et al. (2024) Inhibition of mitochondrial folate metabolism drives differentiation through mTORC1-mediated purine sensing. Nature Communications, 15, 1931. (doi: 10.1038/s41467-024-46114-0) (PMID:38431691) (PMCID:PMC10908830)
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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.
| Item Type: | Articles |
|---|---|
| Additional Information: | This work was supported by Cancer Research UK Glasgow Centre (A25142), Cancer Research UK (C57352/A29754), The Kay Kendall Leukemia Fund (KKL1069), Blood Cancer UK (formerly Bloodwise; Ref 18006), The Howat Foundation, Tenovus Scotland and Friends of Paul O’Gorman Leukaemia Research Centre (all to G.V.H.); NHSGGC Endowment Fellowship (GN21ON384) to M.M.Z. and Cancer Research UK to D.S.2 (A17196 and A31287) and A.V. (A17196 and A21140). M.M.Z. was supported by a Cancer Research UK PhD scholarship (A25142). |
| Status: | Published |
| Refereed: | Yes |
| Glasgow Author(s) Enlighten ID: | Dunn, Mrs Karen and Dawson, Ms Amy and Sumpton, Dr David and Ianniciello, Ms Angela and Sarnello, Daniele and Vazquez, Alexei and Rattigan, Dr Kevin and Helgason, Professor Vignir and Zarou, Miss Martha and Copland, Professor Mhairi |
| Authors: | Zarou, M. M., Rattigan, K. M., Sarnello, D., Shokry, E., Dawson, A., Ianniciello, A., Dunn, K., Copland, M., Sumpton, D., Vazquez, A., and Helgason, V. |
| College/School: | College of Medical Veterinary and Life Sciences College of Medical Veterinary and Life Sciences > School of Biodiversity, One Health & Veterinary Medicine College of Medical Veterinary and Life Sciences > School of Cancer Sciences |
| Journal Name: | Nature Communications |
| Publisher: | Nature Research |
| ISSN: | 2041-1723 |
| ISSN (Online): | 2041-1723 |
| Copyright Holders: | Copyright: © The Author(s) 2024 |
| First Published: | First published in Nature Communications 15: 1931 |
| Publisher Policy: | Reproduced under a Creative Commons licence |
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