WEKO3
-
RootNode
アイテム
Thiopurine-mediated impairment of hematopoietic stem and leukemia cells in Nudt15R138C knock-in mice.
http://hdl.handle.net/10422/00012580
http://hdl.handle.net/10422/000125801706e9aa-7e81-4154-8d61-b2eea3d0b6fb
| 名前 / ファイル | ライセンス | アクション |
|---|---|---|
s41375-019-0583-9 (10.0 MB)
|
© The Author(s), under exclusive licence to Springer Nature Limited 2019
|
|
|
Supplementary information_s41375-019-0583-9 (2.4 MB)
|
© The Author(s), under exclusive licence to Springer Nature Limited 2019
|
| Item type | 学術雑誌論文 / Journal Article(1) | |||||
|---|---|---|---|---|---|---|
| 公開日 | 2019-11-25 | |||||
| タイトル | ||||||
| タイトル | Thiopurine-mediated impairment of hematopoietic stem and leukemia cells in Nudt15R138C knock-in mice. | |||||
| 言語 | ||||||
| 言語 | eng | |||||
| 資源タイプ | ||||||
| 資源タイプ識別子 | http://purl.org/coar/resource_type/c_6501 | |||||
| 資源タイプ | journal article | |||||
| 著者 |
TATSUMI, Goichi
× TATSUMI, Goichi× KAWAHARA, Masahiro× IMAI, Takayuki× NISHISHITA-ASAI, Ai× NISHIDA, Atsushi× INATOMI, Osamu× YOKOYAMA, Akihiko× KAKUTA, Yoichi× KITO, Katsuyuki× ANDOH, Akira |
|||||
| 著者別名 |
辰巳, 剛一
× 辰巳, 剛一× 河原, 真大× 今井, 隆行× 浅井, 愛× 西田, 淳史× 稲富, 理× 木藤, 克之× 安藤, 朗 |
|||||
| 抄録 | ||||||
| 内容記述タイプ | Abstract | |||||
| 内容記述 | 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. | |||||
| 書誌情報 |
en : Leukemia 発行日 2019-10-24 |
|||||
| 出版者 | ||||||
| 出版者 | Nature Publishing Group | |||||
| ISSN | ||||||
| 収録物識別子タイプ | ISSN | |||||
| 収録物識別子 | 1476-5551 | |||||
| PMID | ||||||
| 関連タイプ | isVersionOf | |||||
| 識別子タイプ | PMID | |||||
| 関連識別子 | 31645647 | |||||
| DOI | ||||||
| 関連タイプ | isVersionOf | |||||
| 識別子タイプ | DOI | |||||
| 関連識別子 | https://doi.org/10.1038/s41375-019-0583-9 | |||||
| 関連名称 | 10.1038/s41375-019-0583-9 | |||||
| 権利 | ||||||
| 権利情報 | © The Author(s), under exclusive licence to Springer Nature Limited 2019 | |||||
| 著者版フラグ | ||||||
| 出版タイプ | AM | |||||
| 出版タイプResource | http://purl.org/coar/version/c_ab4af688f83e57aa | |||||
| 資源タイプ | ||||||
| 内容記述タイプ | Other | |||||
| 内容記述 | Journal Article | |||||
