The NUDIX hydrolase NUDT5 regulates thiopurine metabolism and cytotoxicity.

Maud Maillard,Rina Nishii,Hieu S Vu,Kashi R Bhattarai,Wenjian Yang,Jing Li,Ute Hofmann,Daniel Savic,Smita Bhatia,Matthias Schwab,Min Ni,Jun J Yang
{"title":"The NUDIX hydrolase NUDT5 regulates thiopurine metabolism and cytotoxicity.","authors":"Maud Maillard,Rina Nishii,Hieu S Vu,Kashi R Bhattarai,Wenjian Yang,Jing Li,Ute Hofmann,Daniel Savic,Smita Bhatia,Matthias Schwab,Min Ni,Jun J Yang","doi":"10.1172/jci190443","DOIUrl":null,"url":null,"abstract":"Thiopurines are anticancer agents used for the treatment of leukemia and autoimmune diseases. These purine analogs are characterized by a narrow therapeutic index because of the risk of myelosuppression. With the discovery of NUDIX hydrolase 15 (NUDT15) as a major modulator of thiopurine metabolism and toxicity, we sought to comprehensively examine all members of the NUDIX hydrolase family for their effect on the pharmacologic effects of thiopurine. By performing a NUDIX-targeted CRISPR/Cas9 screen in leukemia cells, we identified NUDT5, whose depletion led to drastic thiopurine resistance. NUDT5 deficiency resulted in a nearly complete depletion of active metabolites of thiopurine and the loss of thioguanine incorporation into DNA. Mechanistically, NUDT5 deletion resulted in substantial alteration in purine nucleotide biosynthesis, as determined by steady-state metabolomics profiling. Stable isotope tracing demonstrated that the loss of NUDT5 was linked to a marked suppression of the purine salvage pathway but with minimal effects on purine de novo synthesis. Finally, we comprehensively identified germline genetic variants in NUDT5 associated with thiopurine-induced myelosuppression in 582 children with acute lymphoblastic leukemia. Collectively, these results pointed to NUDT5 as a key regulator of the thiopurine response primarily through its effects on purine homeostasis, highlighting its potential to inform individualized thiopurine therapy.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"9 1","pages":""},"PeriodicalIF":0.0000,"publicationDate":"2025-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"The Journal of Clinical Investigation","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.1172/jci190443","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"","JCRName":"","Score":null,"Total":0}
引用次数: 0

Abstract

Thiopurines are anticancer agents used for the treatment of leukemia and autoimmune diseases. These purine analogs are characterized by a narrow therapeutic index because of the risk of myelosuppression. With the discovery of NUDIX hydrolase 15 (NUDT15) as a major modulator of thiopurine metabolism and toxicity, we sought to comprehensively examine all members of the NUDIX hydrolase family for their effect on the pharmacologic effects of thiopurine. By performing a NUDIX-targeted CRISPR/Cas9 screen in leukemia cells, we identified NUDT5, whose depletion led to drastic thiopurine resistance. NUDT5 deficiency resulted in a nearly complete depletion of active metabolites of thiopurine and the loss of thioguanine incorporation into DNA. Mechanistically, NUDT5 deletion resulted in substantial alteration in purine nucleotide biosynthesis, as determined by steady-state metabolomics profiling. Stable isotope tracing demonstrated that the loss of NUDT5 was linked to a marked suppression of the purine salvage pathway but with minimal effects on purine de novo synthesis. Finally, we comprehensively identified germline genetic variants in NUDT5 associated with thiopurine-induced myelosuppression in 582 children with acute lymphoblastic leukemia. Collectively, these results pointed to NUDT5 as a key regulator of the thiopurine response primarily through its effects on purine homeostasis, highlighting its potential to inform individualized thiopurine therapy.
NUDIX水解酶NUDT5调节硫嘌呤代谢和细胞毒性。
硫嘌呤是用于治疗白血病和自身免疫性疾病的抗癌药物。这些嘌呤类似物的特点是治疗指数较窄,因为有骨髓抑制的风险。随着NUDIX水解酶15 (NUDT15)作为硫嘌呤代谢和毒性的主要调节剂的发现,我们试图全面研究NUDIX水解酶家族的所有成员对硫嘌呤药理作用的影响。通过在白血病细胞中进行nudix靶向CRISPR/Cas9筛选,我们确定了NUDT5,其缺失导致了剧烈的硫嘌呤耐药性。NUDT5缺乏导致硫嘌呤活性代谢物几乎完全耗尽,硫鸟嘌呤并入DNA的损失。从机制上讲,通过稳态代谢组学分析,NUDT5缺失导致嘌呤核苷酸生物合成的实质性改变。稳定同位素示踪表明,NUDT5的缺失与嘌呤回收途径的显著抑制有关,但对嘌呤从头合成的影响很小。最后,我们在582例急性淋巴细胞白血病儿童中全面鉴定了与硫嘌呤诱导的骨髓抑制相关的NUDT5种系遗传变异。总的来说,这些结果表明NUDT5是硫嘌呤反应的关键调节因子,主要通过其对嘌呤稳态的影响,突出了其为个体化硫嘌呤治疗提供信息的潜力。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
求助全文
约1分钟内获得全文 求助全文
来源期刊
自引率
0.00%
发文量
0
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
确定
请完成安全验证×
copy
已复制链接
快去分享给好友吧!
我知道了
右上角分享
点击右上角分享
0
联系我们:info@booksci.cn Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。 Copyright © 2023 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:604180095
Book学术官方微信