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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.

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Title: Increased DNA-incorporated thiopurine metabolite as a possible mechanism for leukocytopenia through cell apoptosis in inflammatory bowel disease patients with NUDT15 mutation.
Authors: Toyonaga, Takahiko, Kobayashi, Taku, Kuronuma, Satoshi, Ueno, Aito, Kiyohara, Hiroki, Okabayashi, Shinji, Takeuchi, Osamu, Redfern, Christopher P. F., Terai, Hideki, Ozaki, Ryo, Sagami, Shintaro, Nakano, Masaru, Coulthard, Sally A., Tanaka, Yoichi, Hibi, Toshifumi
Source: Journal of Gastroenterology; Nov2021, Vol. 56 Issue 11, p999-1007, 9p
Subject Terms: INFLAMMATORY bowel diseases, MONONUCLEAR leukocytes, PYROPTOSIS, ERYTHROCYTES, LEUCOPENIA, CELL death
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. [ABSTRACT FROM AUTHOR]
Copyright of Journal of Gastroenterology is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
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  Data: Increased DNA-incorporated thiopurine metabolite as a possible mechanism for leukocytopenia through cell apoptosis in inflammatory bowel disease patients with NUDT15 mutation.
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  Data: <searchLink fieldCode="AR" term="%22Toyonaga%2C+Takahiko%22">Toyonaga, Takahiko</searchLink><br /><searchLink fieldCode="AR" term="%22Kobayashi%2C+Taku%22">Kobayashi, Taku</searchLink><br /><searchLink fieldCode="AR" term="%22Kuronuma%2C+Satoshi%22">Kuronuma, Satoshi</searchLink><br /><searchLink fieldCode="AR" term="%22Ueno%2C+Aito%22">Ueno, Aito</searchLink><br /><searchLink fieldCode="AR" term="%22Kiyohara%2C+Hiroki%22">Kiyohara, Hiroki</searchLink><br /><searchLink fieldCode="AR" term="%22Okabayashi%2C+Shinji%22">Okabayashi, Shinji</searchLink><br /><searchLink fieldCode="AR" term="%22Takeuchi%2C+Osamu%22">Takeuchi, Osamu</searchLink><br /><searchLink fieldCode="AR" term="%22Redfern%2C+Christopher+P%2E+F%2E%22">Redfern, Christopher P. F.</searchLink><br /><searchLink fieldCode="AR" term="%22Terai%2C+Hideki%22">Terai, Hideki</searchLink><br /><searchLink fieldCode="AR" term="%22Ozaki%2C+Ryo%22">Ozaki, Ryo</searchLink><br /><searchLink fieldCode="AR" term="%22Sagami%2C+Shintaro%22">Sagami, Shintaro</searchLink><br /><searchLink fieldCode="AR" term="%22Nakano%2C+Masaru%22">Nakano, Masaru</searchLink><br /><searchLink fieldCode="AR" term="%22Coulthard%2C+Sally+A%2E%22">Coulthard, Sally A.</searchLink><br /><searchLink fieldCode="AR" term="%22Tanaka%2C+Yoichi%22">Tanaka, Yoichi</searchLink><br /><searchLink fieldCode="AR" term="%22Hibi%2C+Toshifumi%22">Hibi, Toshifumi</searchLink>
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  Data: Journal of Gastroenterology; Nov2021, Vol. 56 Issue 11, p999-1007, 9p
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  Data: <searchLink fieldCode="DE" term="%22INFLAMMATORY+bowel+diseases%22">INFLAMMATORY bowel diseases</searchLink><br /><searchLink fieldCode="DE" term="%22MONONUCLEAR+leukocytes%22">MONONUCLEAR leukocytes</searchLink><br /><searchLink fieldCode="DE" term="%22PYROPTOSIS%22">PYROPTOSIS</searchLink><br /><searchLink fieldCode="DE" term="%22ERYTHROCYTES%22">ERYTHROCYTES</searchLink><br /><searchLink fieldCode="DE" term="%22LEUCOPENIA%22">LEUCOPENIA</searchLink><br /><searchLink fieldCode="DE" term="%22CELL+death%22">CELL death</searchLink>
– Name: Abstract
  Label: Abstract
  Group: Ab
  Data: 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 dTG<superscript>PBMC</superscript> 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<superscript>+</superscript> T lymphocytes with 6-thioguanine (6-TG). Results: dTG<superscript>PBMC</superscript> was significantly higher in NUDT15 variants than in non-variants. dTG<superscript>PBMC</superscript>, but not 6-TGN<superscript>RBC</superscript>, 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. [ABSTRACT FROM AUTHOR]
– Name: Abstract
  Label:
  Group: Ab
  Data: <i>Copyright of Journal of Gastroenterology is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract.</i> (Copyright applies to all Abstracts.)
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        Value: 10.1007/s00535-021-01820-0
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        Text: English
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    Subjects:
      – SubjectFull: INFLAMMATORY bowel diseases
        Type: general
      – SubjectFull: MONONUCLEAR leukocytes
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      – SubjectFull: LEUCOPENIA
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              Text: Nov2021
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