Increased DNA-incorporated thiopurine metabolite as a possible mechanism for leukocytopenia through cell apoptosis in inflammatory bowel disease patients with NUDT15 mutation

Takahiko Toyonaga, Taku Kobayashi, Satoshi Kuronuma, Aito Ueno, Hiroki Kiyohara, Shinji Okabayashi, Osamu Takeuchi, Christopher P.F. Redfern, Hideki Terai, Ryo Ozaki, Shintaro Sagami, Masaru Nakano, Sally A. Coulthard, Yoichi Tanaka, Toshifumi Hibi

Research output: Contribution to journalArticlepeer-review

Abstract

Background and Aims: Polymorphisms in the nucleotide diphosphate-linked moiety X-type motif 15 (NUDT15) gene are associated with thiopurine-induced leukopenia in patients with inflammatory bowel disease (IBD). NUDT15-associated subcellular thiopurine metabolism has not been investigated in primary lymphocytes. We hypothesized that NUDT15 mutation increases DNA-incorporated deoxythioguanosine (dTG) and induces apoptosis in lymphocytes. Methods: DNA-incorporated dTG in peripheral blood mononuclear cells (PBMCs) and 6-thioguanine nucleotides (6-TGN) in red blood cells were measured in patients with IBD undergoing thiopurine treatment. The association of a single nucleotide polymorphism for NUDT15 (rs116855232) with dTGPBMC was examined. The pro-apoptotic effect of DNA-incorporated dTG was examined ex vivo in association with NUDT15 genotypes by co-culturing patient-derived peripheral CD4+ T lymphocytes with 6-thioguanine (6-TG). Results: dTGPBMC was significantly higher in NUDT15 variants than in non-variants. dTGPBMC, but not 6-TGNRBC, negatively correlated with peripheral lymphocyte counts (r = – 0.31 and – 0.12, p = 0.012 and 0.173, respectively). DNA-incorporated dTG significantly accumulated to a greater extent in lymphocytes from NUDT15 variants when co-cultured with 6-TG ex vivo than in those from non-variants and was associated with decreased proliferation and increased apoptosis. Conclusion: Increased DNA-incorporated dTG may be responsible for thiopurine-induced leukocytopenia through cell apoptosis in IBD patients with NUDT15 mutation.

Original languageEnglish
JournalJournal of gastroenterology
DOIs
Publication statusAccepted/In press - 2021
Externally publishedYes

Keywords

  • Inflammatory bowel disease
  • NUDT15
  • Thiopurine

ASJC Scopus subject areas

  • Gastroenterology

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