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While leukemogenesis occurs in the hypoxic bone marrow, the therapeutic tractability of the hypoxia-inducible factor (HIF) system remains undefined. Given that inactivation of HIF-1\u03b1\/HIF-2\u03b1 promotes AML, a possible clinical strategy is to target the HIF-prolyl hydroxylases (PHDs), which promote HIF-1\u03b1\/HIF-2\u03b1 degradation. Here, we reveal that genetic inactivation of <jats:italic>Phd1<\/jats:italic>\/<jats:italic>Phd2<\/jats:italic> hinders AML initiation and progression, without impacting normal hematopoiesis. We investigated clinically used PHD inhibitors and a new selective PHD inhibitor (IOX5), to stabilize HIF-\u03b1 in AML cells. PHD inhibition compromises AML in a HIF-1\u03b1-dependent manner to disable pro-leukemogenic pathways, re-program metabolism and induce apoptosis, in part via upregulation of BNIP3. Notably, concurrent inhibition of BCL-2 by venetoclax potentiates the anti-leukemic effect of PHD inhibition. Thus, PHD inhibition, with consequent HIF-1\u03b1 stabilization, is a promising nontoxic strategy for AML, including in combination with venetoclax.<\/jats:p>","DOI":"10.1038\/s43018-024-00761-w","type":"journal-article","created":{"date-parts":[[2024,4,18]],"date-time":"2024-04-18T10:19:29Z","timestamp":1713435569000},"page":"916-937","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":43,"title":["The selective prolyl hydroxylase inhibitor IOX5 stabilizes HIF-1\u03b1 and compromises development and progression of acute myeloid leukemia"],"prefix":"10.1038","volume":"5","author":[{"given":"Hannah","family":"Lawson","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James 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