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Polymorphisms in methylenetetrahydrofolate reductase and methotrexate sensitivity in childhood acute lymphoblastic leukemia

Leukemia volume 16, pages 764–765 (2002)Cite this article

In view of the importance of methotrexate (MTX) therapy in the treatment of childhood ALL particularly during the consolidation and maintenance phases of treatment, identifying parameters associated with MTX sensitivity and resistance have direct relevance to the treatment of patients with ALL. Pharmacologic and biologic parameters which correlate with clinical MTX sensitivity and resistance in the treatment of ALL include: (1) altered intracellular MTX transport via the reduced folate carrier (RFC); (2) generation of long-chain MTX-polyglutamates catalyzed by folypolyglutamate synthase (FPGS); (3) levels of dihydrofolate reductase (DHFR), the primary target of MTX inhibition; and (4) the relationship of MTX sensitivity and leukemia cytogenetics including hyperdiploidy.1,2,3,4,5,6 It is conceivable that additional factors may also be determinants of MTX response.

The main mechanism of action of MTX as an anti-folate agent, results in the depletion of metabolically active pools of tetrahydrofolate cofactors with a suppression of folate-dependent synthesis of DNA, RNA and protein and thus, it is conceivable that alterations in reduced folate pools may lead to altered MTX sensitivity. Recently, polymorphisms of 5,10-methylenetetrahydrofolate reductase (MTHFR) (gene localized to 1p36.3), an enzyme which catalyzes the conversion of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, the main circulating form of reduce folates, have been identified. Reduced activity of the MTHFR C677T allele (with the resultant substitution of valine for alanine), in both the heterozygous and homozygous state has been linked to hyperhomocysteinemia due to folate pool imbalances.7

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Acknowledgements

Supported by The Children's Research Center of Michigan, Art Gagnon Memorial Fund, BPCT Golf Charity, and Leukemia Research, Life, Inc. (Detroit, MI).

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Authors and Affiliations

  1. Children's Hospital of Michigan, Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI, USA

    JW Taub, LH Matherly & Y Ravindranath

  2. University Hospital, Vrije Universiteit, Amsterdam, The Netherlands

    G-J L Kaspers, MG Rots & CH Zantwijk

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Taub, J., Matherly, L., Ravindranath, Y. et al. Polymorphisms in methylenetetrahydrofolate reductase and methotrexate sensitivity in childhood acute lymphoblastic leukemia. Leukemia 16, 764–765 (2002). https://doi.org/10.1038/sj.leu.2402428

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