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PTEN-loss drives AKT\/mTORC1 signaling to promote leukemic cell growth. We find that PTEN-loss in T-ALL confers dependence on the guanylate nucleotide synthesis enzyme inosine 5\u2019-monophosphate dehydrogenase (IMPDH) for cell growth and viability. This metabolic vulnerability is dependent on sustained AKT\/mTORC1 signaling and can be exploited using clinically approved IMPDH inhibitors to selectively kill PTEN-deficient T-ALL cells, and extend survival in genetic and xenograft T-ALL models in mice. Mechanistically, IMPDH inhibitors cause DNA replication stress early on, followed by DNA damage. In contrast to treatment with mTORC1 inhibitors, these events culminate in robust and selective cell death in PTEN-deficient T-ALL cells. We also find that p53 enhances, but is not required for, IMPDH inhibitor-induced cell death. These findings reveal a targetable metabolic vulnerability in T-ALL, providing rationale for repurposing clinically approved IMPDH inhibitors.<\/jats:p>","DOI":"10.1038\/s44321-026-00533-2","type":"journal-article","created":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T12:02:17Z","timestamp":1792065737000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["PTEN-loss confers dependence on the guanylate synthesis enzyme IMPDH in T-cell acute lymphoblastic leukemia"],"prefix":"10.1038","author":[{"given":"Rayees A","family":"Padder","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1013-2328","authenticated-orcid":false,"given":"Thu","family":"Le Le","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emily","family":"Hyde","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3570-1774","authenticated-orcid":false,"given":"Maria E D","family":"Rubio","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric","family":"Chiles","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0267-1150","authenticated-orcid":false,"given":"Jay N","family":"Joshi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8295-9650","authenticated-orcid":false,"given":"Nanda","family":"Singh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6163-198X","authenticated-orcid":false,"given":"Masuda","family":"Akther","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Namratha","family":"Sheshadri","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kelly","family":"Mulraney","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei-Xing","family":"Zong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoyang","family":"Su","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1768-5969","authenticated-orcid":false,"given":"Daniel","family":"Herranz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4369-6074","authenticated-orcid":false,"given":"Alexander J","family":"Valvezan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,10,15]]},"reference":[{"key":"533_CR1","doi-asserted-by":"crossref","first-page":"1323","DOI":"10.1126\/science.1228792","volume":"339","author":"I Ben-Sahra","year":"2013","unstructured":"Ben-Sahra I, Howell JJ, Asara JM, Manning BD (2013) Stimulation of de novo pyrimidine synthesis by growth signaling through mTOR and S6K1. 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