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

Lookup NU author(s): Dr Chris RedfernORCiD, Dr Sally Coulthard

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This is the authors' accepted manuscript of an article that has been published in its final definitive form by Springer Japan, 2021.

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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 inflammatory bowel disease undergoing thiopurine treatment. The association of a single nucleotide polymorphism for NUDT15 (rs116855232) with dTG^PBMC 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: dTG^PBMC was significantly higher in NUDT15 variants than in non-variants. dTG^PBMC, but not 6-TGN^RBC, 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 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

Publication metadata

Author(s): Toyonaga K, Kobayashi T, Kuronuma S, Ueno A, Kiyohara H, Okabayashi S, Takeuchi O, Redfern CPF, Terai H, Ozaki R, Sagami S, Nakano M, Coulthard SA, Tanaka Y, Hibi T

Publication type: Article

Publication status: Published

Journal: Journal of Gastroenterology

Year: 2021

Volume: 56

Pages: 999-1007

Print publication date: 01/11/2021

Online publication date: 04/09/2021

Acceptance date: 21/08/2021

Date deposited: 28/08/2021

ISSN (print): 0944-1174

ISSN (electronic): 1435-5922

Publisher: Springer Japan

URL: https://doi.org/10.1007/s00535-021-01820-0

DOI: 10.1007/s00535-021-01820-0

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