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

被引:2
|
作者
Zarou, Martha M. [1 ]
Rattigan, Kevin M. [1 ]
Sarnello, Daniele [1 ]
Shokry, Engy [2 ]
Dawson, Amy [1 ]
Ianniciello, Angela [1 ]
Dunn, Karen [3 ]
Copland, Mhairi [3 ]
Sumpton, David [2 ]
Vazquez, Alexei [1 ]
Helgason, G. Vignir [1 ]
机构
[1] Univ Glasgow, Wolfson Wohl Canc Res Ctr, Sch Canc Sci, Glasgow G61 1QH, Scotland
[2] Canc Res UK Scotland Inst, Glasgow G61 1BD, Scotland
[3] Univ Glasgow, Paul OGorman Leukaemia Res Ctr, Sch Canc Sci, Glasgow G12 0ZD, Scotland
关键词
CHRONIC MYELOID-LEUKEMIA; CHRONIC MYELOGENOUS LEUKEMIA; ONE-CARBON METABOLISM; STEM-CELLS; BCR-ABL; IMATINIB MESYLATE; KINASE-ACTIVITY; METHOTREXATE; GLYCINE; SERINE;
D O I
10.1038/s41467-024-46114-0
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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. The role of folate metabolism in leukemic stem cells remains understudied. Here, the authors show that inhibition of mitochondrial folate metabolism leads to differentiation of leukemic cells through depletion of purines and suppression of mTORC1.
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页数:18
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