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The effects of inherited NUDT15 polymorphisms on thiopurine active metabolites in Japanese children with acute lymphoblastic leukemia

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  • Takaya Moriyama
  • Rina Nishii
  • Ting-Nien Lin
  • Kentaro Kihira
  • Hidemi Toyoda
  • Nersting Jacob
  • Motohiro Kato
  • Katsuyoshi Koh
  • Hiroto Inaba
  • Atsushi Manabe
  • Kjeld Schmiegelow
  • Jun J Yang
  • Hiroki Hori
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Thiopurines [e.g. mercaptopurine (MP)] are widely used as chemotherapeutic agents in the treatment of pediatric acute lymphoblastic leukemia with dose-limiting hematopoietic toxicity. Recently, germline variants in NUDT15 have been identified as a major genetic cause for MP-related bone marrow suppression, and there is increasing interest in the clinical implementation of NUDT15 genotype-guided MP dose individualization. Therefore, we sought to evaluate the effects of NUDT15 on thiopurine metabolism and identify pharmacologic markers to inform NUDT15 genotype-guided MP dosing. In 55 Japanese children with acute lymphoblastic leukemia, we simultaneously measured both thioguanine nucleotides (TGN) in red blood cells and DNA-incorporated thioguanine (DNA-TG) in white blood cells. TGN levels were significantly lower in patients with NUDT15 deficiency, likely because of toxicity-related MP dose reduction. In contrast, when exposed to the same dose of MP, DNA-TG accumulated more efficiently in vivo with increasing number of risk alleles in NUDT15 (P=4.0×10). Cytosolic TGN and nuclear DNA-TG were correlated positively with each other across genotype groups (P=6.5×10), but the ratio of DNA-TG to TGN was significantly higher in NUDT15-deficient patients (P=3.6×10), consistent with excessive MP activation. In conclusion, our results suggest that DNA-TG is a more relevant MP metabolite than TGN to inform NUDT15 genotype-guided dose adjustments.

Original languageEnglish
JournalPharmacogenetics and Genomics
Volume27
Issue number6
Pages (from-to)236-239
Number of pages4
ISSN1744-6872
DOIs
Publication statusPublished - Jun 2017

    Research areas

  • Journal Article

ID: 52772900