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Acute Leukemias

Folate restriction and methylenetetrahydrofolate reductase 677T polymorphism decreases adoMet synthesis via folate-dependent remethylation in human-transformed lymphoblasts

Leukemia volume 21, pages 651–658 (2007)Cite this article

Abstract

The homozygous mutation (677TT) in the methylenetetrahydrofolate reductase (MTHFR) gene reduces enzyme activity and alters cellular folate composition. Previous epidemiological studies reported a potential protective effect of MTHFR677C → T against acute lymphocytic leukemia and malignant lymphoma, but the mechanism remains to be determined. We investigated the biochemical impacts of MTHFR677C → T on cellular S-adenosyl methionine (adoMet) synthesis, global DNA methylation, and de novo purine synthesis, all of which are potential regulatory pathways involved in tumorigenesis. Metabolic fluxes of homocysteine remethylation and de novo purine synthesis were compared between Epstein–Barr virus-transformed lymphoblasts expressing MTHFR 677C and MTHFR 677T using stable isotopic tracers and GCMS. MTHFR TT genotype significantly reduced folate-dependent remethylation under folate restriction, reflecting limited methylated folates under folate restriction. Data also suggested increased formylated folate pool and increased purine synthesis when folate is adequate. The impacts of MTHFR 677T polymorphism appeared closely related to folate status, and such alterations may modulate metabolic pathways involved in cancer onset/progression. The advantage of de novo purine synthesis found in the MTHFR TT genotype may account for the protective effect of MTHFR in hematological malignancies. These transformed cells are potential models for studying the consequences of human genetic variation and cancer pathogenesis.

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Acknowledgements

This project was supported by National Science Council in Taiwan (NSC 93-2313-B005-083 Chiang E-P) and Department of Health in Taiwan (DOH 95-TD-D-113-009 Chiang E-P). This material was presented in part in the 2005 American Association for Cancer Research annual meeting.

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  1. Department of Food Science and Biotechnology, National Chung Hsing University, Taichung, Taiwan

    E-P Chiang, Y-C Wang & F-Y Tang

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Correspondence to E-P Chiang.

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Chiang, EP., Wang, YC. & Tang, FY. Folate restriction and methylenetetrahydrofolate reductase 677T polymorphism decreases adoMet synthesis via folate-dependent remethylation in human-transformed lymphoblasts. Leukemia 21, 651–658 (2007). https://doi.org/10.1038/sj.leu.2404575

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