{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T18:44:20Z","timestamp":1790016260555,"version":"4.0.1"},"reference-count":24,"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\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,7,15]]},"abstract":"<jats:p>\n                    Purine nucleotides are critical for nucleic acid synthesis, signaling, and cellular metabolism. Thiopurines (TPs), including 6-mercaptopurine and 6-thioguanine, are cornerstone agents for the treatment of acute lymphoblastic leukemia (ALL). TP efficacy and cytotoxicity depend on the metabolism and intracellular activation of TPs, a process influenced by pharmacogenes such as thiopurine-S methyltransferase (\n                    <jats:italic>TPMT<\/jats:italic>\n                    ) and NUDIX (nucleoside diphosphates linked to moiety-X) hydrolase 15 (\n                    <jats:italic>NUDT15<\/jats:italic>\n                    ). In this issue of the\n                    <jats:italic>JCI<\/jats:italic>\n                    , Maillard et al. identified\n                    <jats:italic>NUDT5<\/jats:italic>\n                    as a determinant of TP pharmacology. They demonstrated that loss of\n                    <jats:italic>NUDT5<\/jats:italic>\n                    conferred TP resistance by impairing drug activation and DNA damage responses. Metabolomics studies by Maillard and others revealed that NUDT5 may regulate the balance between the de novo purine synthesis and salvage pathways. Clinically,\n                    <jats:italic>NUDT5<\/jats:italic>\n                    expression variants were associated with altered TP tolerance. These findings position\n                    <jats:italic>NUDT5<\/jats:italic>\n                    as a key modulator of nucleotide metabolism and TP efficacy, with potential implications for pharmacogenomics-guided therapy optimization in ALL.\n                  <\/jats:p>","DOI":"10.1172\/jci194434","type":"journal-article","created":{"date-parts":[[2025,7,14]],"date-time":"2025-07-14T18:00:41Z","timestamp":1752516041000},"source":"Crossref","is-referenced-by-count":6,"title":["The NUDIX hydrolase NUDT5 influences purine nucleotide metabolism and thiopurine pharmacology"],"prefix":"10.1172","volume":"135","author":[{"given":"Leo","family":"Kager","sequence":"first","affiliation":[{"name":"St. Anna Children\u2019s Hospital, Vienna, Austria."},{"name":"Medical University of Vienna, Department of Pediatrics and Adolescent Medicine, Vienna, Austria."},{"name":"St. Anna Children\u2019s Cancer Research Institute, Vienna, Austria."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kaan","family":"Boztug","sequence":"additional","affiliation":[{"name":"Medical University of Vienna, Department of Pediatrics and Adolescent Medicine, Vienna, Austria."},{"name":"St. Anna Children\u2019s Cancer Research Institute, Vienna, Austria."},{"name":"Research Center for Molecular Medicine (CeMM) of the Austrian Academy of Sciences, Vienna, Austria."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"232","published-online":{"date-parts":[[2025,7,15]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2024.06.015"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2024.05.011"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1126\/science.2649979"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1038\/s41572-024-00525-x"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1038\/nrc2292"},{"key":"B6","unstructured":"PharmGKB: The Pharmacogenomics Knowledge Base. Thiopurine Pathway, Pharmacokinetics\/Pharmacodynamics. https:\/\/www.pharmgkb.org\/pathway\/PA2040 Updated April 10, 2025. Accessed June 13, 2025"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1038\/s41375-022-01591-4"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(17)30154-7"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.23.01286"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1093\/jnci\/djae004"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.3324\/haematol.11239"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1038\/leu.2009.42"},{"key":"B13","unstructured":"Clinical Pharmacogenetics Implementation Consortium. CPIC. Guideline for Thiopurines and TPMT and NUDT15 (CPIC\u00ae). https:\/\/cpicpgx.org\/guidelines\/guideline-for-thiopurines-and-tpmt\/ Updated March 2024. Accessed June 13, 2025"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1038\/nature25186"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1182\/blood.2019002499"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1038\/nm.3840"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.3324\/haematol.2017.176362"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1172\/JCI190443"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-017-01642-w"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1038\/s43018-020-00124-1"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1038\/nbt.3437"},{"key":"B22","doi-asserted-by":"crossref","unstructured":"Strefeler A, et al. Uridine-sensitized screening identifies genes and metabolic regulators of nucleotide synthesis. [preprint]. https:\/\/doi.org\/10.1101\/2025.03.11.642569 Posted on bioRxiv March 13, 2025","DOI":"10.1101\/2025.03.11.642569"},{"key":"B23","doi-asserted-by":"crossref","unstructured":"Wu Z, et al. NUDT5 regulates purine metabolism and thiopurine sensitivity by interacting with PPAT. [preprint]. https:\/\/doi.org\/10.1101\/2025.03.29.646096 Posted on bioRxiv April 1, 2025","DOI":"10.1101\/2025.03.29.646096"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2003-12-4306"}],"container-title":["Journal of Clinical Investigation"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.jci.org\/articles\/view\/194434\/files\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,19]],"date-time":"2026-05-19T17:16:12Z","timestamp":1779210972000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.jci.org\/articles\/view\/194434"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,7,15]]},"references-count":24,"journal-issue":{"issue":"14","published-online":{"date-parts":[[2025,5,20]]},"published-print":{"date-parts":[[2025,7,15]]}},"alternative-id":["10.1172\/JCI194434"],"URL":"https:\/\/doi.org\/10.1172\/jci194434","relation":{},"ISSN":["1558-8238"],"issn-type":[{"value":"1558-8238","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,7,15]]},"article-number":"e194434"}}