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

التفاصيل البيبلوغرافية
العنوان: Inhibition of mitochondrial folate metabolism drives differentiation through mTORC1 mediated purine sensing.
المؤلفون: Zarou MM; Wolfson Wohl Cancer Research Centre, School of Cancer Sciences, University of Glasgow, Glasgow, G61 1QH, UK., Rattigan KM; Wolfson Wohl Cancer Research Centre, School of Cancer Sciences, University of Glasgow, Glasgow, G61 1QH, UK., Sarnello D; Wolfson Wohl Cancer Research Centre, School of Cancer Sciences, University of Glasgow, Glasgow, G61 1QH, UK., Shokry E; Cancer Research UK Scotland Institute, Glasgow, G61 1BD, UK., Dawson A; Wolfson Wohl Cancer Research Centre, School of Cancer Sciences, University of Glasgow, Glasgow, G61 1QH, UK., Ianniciello A; Wolfson Wohl Cancer Research Centre, School of Cancer Sciences, University of Glasgow, Glasgow, G61 1QH, UK., Dunn K; Paul O'Gorman Leukaemia Research Centre, School of Cancer Sciences, University of Glasgow, Glasgow, G12 0ZD, UK., Copland M; Paul O'Gorman Leukaemia Research Centre, School of Cancer Sciences, University of Glasgow, Glasgow, G12 0ZD, UK., Sumpton D; Cancer Research UK Scotland Institute, Glasgow, G61 1BD, UK., Vazquez A; Wolfson Wohl Cancer Research Centre, School of Cancer Sciences, University of Glasgow, Glasgow, G61 1QH, UK. avazque1@protonmail.com., Helgason GV; Wolfson Wohl Cancer Research Centre, School of Cancer Sciences, University of Glasgow, Glasgow, G61 1QH, UK. vignir.helgason@glasgow.ac.uk.
المصدر: Nature communications [Nat Commun] 2024 Mar 02; Vol. 15 (1), pp. 1931. Date of Electronic Publication: 2024 Mar 02.
نوع المنشور: Journal Article
اللغة: English
بيانات الدورية: Publisher: Nature Pub. Group Country of Publication: England NLM ID: 101528555 Publication Model: Electronic Cited Medium: Internet ISSN: 2041-1723 (Electronic) Linking ISSN: 20411723 NLM ISO Abbreviation: Nat Commun Subsets: MEDLINE
أسماء مطبوعة: Original Publication: [London] : Nature Pub. Group
مواضيع طبية MeSH: Leukemia, Myeloid* , Leukemia, Myelogenous, Chronic, BCR-ABL Positive*/drug therapy, Humans ; Mechanistic Target of Rapamycin Complex 1 ; AMP-Activated Protein Kinases ; Purines/therapeutic use ; Purine Nucleotides ; Folic Acid/metabolism
مستخلص: 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.
(© 2024. The Author(s).)
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معلومات مُعتمدة: C57352/A29754 Cancer Research UK (CRUK); A25142 Cancer Research UK (CRUK); A17196 Cancer Research UK (CRUK); A31287 Cancer Research UK (CRUK); A17196 Cancer Research UK (CRUK); A21140 Cancer Research UK (CRUK); KKL1069 Kay Kendall Leukaemia Fund (KKLF); 18006 Bloodwise; GN21ON384 NHS Greater Glasgow and Clyde
المشرفين على المادة: EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1)
EC 2.7.11.31 (AMP-Activated Protein Kinases)
0 (Purines)
0 (Purine Nucleotides)
935E97BOY8 (Folic Acid)
تواريخ الأحداث: Date Created: 20240302 Date Completed: 20240305 Latest Revision: 20240306
رمز التحديث: 20240307
مُعرف محوري في PubMed: PMC10908830
DOI: 10.1038/s41467-024-46114-0
PMID: 38431691
قاعدة البيانات: MEDLINE
الوصف
تدمد:2041-1723
DOI:10.1038/s41467-024-46114-0