Thiopurine-mediated impairment of hematopoietic stem and leukemia cells in Nudt15 R138C knock-in mice

Goichi Tatsumi, Masahiro Kawahara, Takayuki Imai, Ai Nishishita-Asai, Atsushi Nishida, Osamu Inatomi, Akihiko Yokoyama, Yoichi Kakuta, Katsuyuki Kito, Akira Andoh

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Abstract

Thiopurines are widely used as antileukemia agents and immunosuppressants. Recent large-scale clinical studies revealed a strong association between the NUDT15 p.Arg139Cys (NUDT15R139C) polymorphism and severe thiopurine-induced leukocytopenia. We established knock-in mice harboring p.Arg138Cys (Nudt15R138C), which corresponds to the human polymorphism. A clinically relevant dose of mercaptopurine (MP) induced lethal cytopenia in Nudt15R138C-harboring mice. MP dose reduction attenuated the hematopoietic toxicity, phenocopying clinical observations and providing Nudt15 genotype-based tolerable doses of MP. High-dose MP induced acute damage to hematopoietic stem and progenitor cells (HSPCs) in Nudt15R138C/R138C mice. A competitive transplantation assay revealed that not only Nudt15R138C/R138C HSPCs, but also Nudt15+/R138C HSPCs suffered stronger damage than Nudt15+/+ HSPCs, even by lower-dose MP, after long-term administration. In a Nudt15 genotype-based posttransplantation leukemia recurrence model generated by bone marrow replacement with congenic wild-type cells and a small number of leukemia stem cells, MP prolonged the survival of mice with posttransplantation Nudt15R138C/R138C leukemia recurrence. In conclusion, our model will facilitate NUDT15 genotype-based precision medicine by providing safer estimates for MP dosing, and our findings highlighted the high susceptibility of hematopoietic stem cells to MP and suggested that exploiting thiopurine toxicity might be a novel treatment approach for leukemia in NUDT15R139C-harboring patients.

Original languageEnglish
Pages (from-to)882-894
Number of pages13
JournalLeukemia
Volume34
Issue number3
DOIs
Publication statusPublished - 2020 Mar 1

ASJC Scopus subject areas

  • Hematology
  • Oncology
  • Cancer Research

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    Tatsumi, G., Kawahara, M., Imai, T., Nishishita-Asai, A., Nishida, A., Inatomi, O., Yokoyama, A., Kakuta, Y., Kito, K., & Andoh, A. (2020). Thiopurine-mediated impairment of hematopoietic stem and leukemia cells in Nudt15 R138C knock-in mice. Leukemia, 34(3), 882-894. https://doi.org/10.1038/s41375-019-0583-9