{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T19:07:01Z","timestamp":1791313621768,"version":"4.3.1"},"reference-count":52,"publisher":"American Society for Clinical Investigation","issue":"14","license":[{"start":{"date-parts":[[2025,7,15]],"date-time":"2025-07-15T00:00:00Z","timestamp":1752537600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["R35 GM141947,R01 CA096670,P30 CA021765"],"award-info":[{"award-number":["R35 GM141947,R01 CA096670,P30 CA021765"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100012524","name":"American Lebanese Syrian Associated Charities","doi-asserted-by":"crossref","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}],"id":[{"id":"10.13039\/100012524","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,7,15]]},"abstract":"<jats:p>\n                    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\n                    <jats:italic>NUDIX<\/jats:italic>\n                    -targeted CRISPR\/Cas9 screen in leukemia cells, we identified\n                    <jats:italic>NUDT5<\/jats:italic>\n                    , 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\n                    <jats:italic>NUDT5<\/jats:italic>\n                    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\n                    <jats:italic>NUDT5<\/jats:italic>\n                    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.\n                  <\/jats:p>","DOI":"10.1172\/jci190443","type":"journal-article","created":{"date-parts":[[2025,7,14]],"date-time":"2025-07-14T18:00:41Z","timestamp":1752516041000},"source":"Crossref","is-referenced-by-count":11,"title":["The NUDIX hydrolase NUDT5 regulates thiopurine metabolism and cytotoxicity"],"prefix":"10.1172","volume":"135","author":[{"given":"Maud","family":"Maillard","sequence":"first","affiliation":[{"name":"Department of Pharmacy and Pharmaceutical Sciences and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rina","family":"Nishii","sequence":"additional","affiliation":[{"name":"Department of Pharmacy and Pharmaceutical Sciences and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hieu 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