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Heterozygosity at the TPMT gene locus, augmented by mutated MTHFR gene, predisposes to 6-MP related toxicities in childhood ALL patients

Leukemia volume 23, pages 971–974 (2009)Cite this article

The clinical relevance of 6-mercaptopurine (6-MP) dose reduction in prevention of thiopurine-induced toxicity is well established in patients homozygous for low activity alleles of thiopurine S-methyltransferase (TPMT) but uncertain in heterozygous individuals. 6-MP is an antimetabolite widely used in the treatment of acute lymphoblastic leukemia (ALL). Its two main modes of action are cytotoxicity, achieved through incorporation of thioguanine nucleotides (TGN) into DNA and RNA, and inhibition of de novo purine synthesis by methyl-thioinosine monophosphate. Metabolic pathways activating 6-MP compete with inactivation pathways catalyzed by xanthine oxidase and TPMT, whose activity is a good prediction factor for the toxicity and effectiveness of the antileukemic thiopurine therapy.1 In Caucasian populations, about 90% have high TPMT activity (wild type), 7–10% intermediate (heterozygous) and 1 in 300 very low or undetectable enzyme activity (mutated homozygous). Decreased TPMT activity is caused by mutations in the TPMT gene, the most prevalent being 460G>A and 719A>G, which are usually inherited together in cis as the *3A allele.2 These polymorphisms destabilize the native structure of the TPMT enzyme, resulting in the formation of misfolded states, which subsequently undergo intracellular degradation. ALL patients with TPMT deficiency tend to respond better to 6-MP therapy because they accumulate TGN in cancer cells, but are at higher risk of developing toxic effects such as hematotoxicity (HET), infections, stomatitis and secondary tumors, because of the high concentration of cytotoxic TGN in normal cells.3 A TPMT cofactor, S-adenosylmethionine (SAM), and its analog from Pseudomonas syringae, sinefungin, prevent degradation of the variant TPMT enzyme in vitro, presumably by stabilizing its native structure.4 Thus, TPMT activity could be affected by endogenous levels of SAM and consequently folate metabolism, including 5,10-methylenetetrahydrofolate reductase (MTHFR),5 which is involved in SAM synthesis. Consequently, decreased MTHFR activity could lead to reduced SAM concentrations and decreased TPMT stability. The MTHFR 677C>T thermolabile variant and 1298A>C variant are associated with decreased MTHFR activity.

To investigate the effect of TPMT haploinsufficiency in heterozygous pediatric ALL patients on thiopurine treatment outcome, we have retrospectively analyzed the association of 6-MP dose reduction and the incidence of 6-MP-induced toxic effects with TPMT and MTHFR genotypes.

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Authors and Affiliations

  1. Department of Clinical Biochemistry, Faculty of Pharmacy, University of Ljubljana, Ljubljana, Slovenia

    N Karas-Kuzelicki, M Milek & I Mlinaric-Rascan

  2. Unit of Oncology and Hematology, University Children's Hospital, University Medical Center, Ljubljana, Slovenia

    J Jazbec

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  1. N Karas-Kuzelicki
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  2. J Jazbec
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  3. M Milek
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  4. I Mlinaric-Rascan
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Correspondence to I Mlinaric-Rascan.

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Supplementary Information accompanies the paper on the Leukemia website (http://www.nature.com/leu)

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Karas-Kuzelicki, N., Jazbec, J., Milek, M. et al. Heterozygosity at the TPMT gene locus, augmented by mutated MTHFR gene, predisposes to 6-MP related toxicities in childhood ALL patients. Leukemia 23, 971–974 (2009). https://doi.org/10.1038/leu.2008.317

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