biostudies-literatureLawson HCancer Research UKBarts CharityMedical Research CouncilBlood Cancer UKWellcome Trust916-937https://www.ebi.ac.uk/biostudies/studies/S-EPMC11208159biostudies-literatureUnknown5(6)Acute myeloid leukemia (AML) is a largely incurable disease, for which new treatments are urgently needed. 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-1α/HIF-2α promotes AML, a possible clinical strategy is to target the HIF-prolyl hydroxylases (PHDs), which promote HIF-1α/HIF-2α degradation. Here, we reveal that genetic inactivation of Phd1/Phd2 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-α in AML cells. PHD inhibition compromises AML in a HIF-1α-dependent manner to disable pro-leukemogenic pathways, re-program metaNature cancerThe selective prolyl hydroxylase inhibitor IOX5 stabilizes HIF-1α and compromises development and progression of acute myeloid leukemia.PMC1120815918004C8717/A18245C29967/ A26787G-00216411041106244/Z/14/Z11047C29967/A14633MR/P010008/20Salah EBowen MO'Carroll DAtwal SDubusse LBellani AArndt CGeorge DSaffoon Nvan de Lagemaat LNLawson HGuitart AVWang LMSo CWEGallipoli PCorner TDurko JDembitz VKabayama YSchofield CJTumber ASchwaller JBrewitz LAllen LFung TKDe Pace ALKranc KRHolt-Martyn JPfalseThe selective prolyl hydroxylase inhibitor IOX5 stabilizes HIF-1α and compromises development and progression of acute myeloid leukemia.Acute myeloid leukemia (AML) is a largely incurable disease, for which new treatments are urgently needed. 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-1α/HIF-2α promotes AML, a possible clinical strategy is to target the HIF-prolyl hydroxylases (PHDs), which promote HIF-1α/HIF-2α degradation. Here, we reveal that genetic inactivation of Phd1/Phd2 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-α in AML cells. PHD inhibition compromises AML in a HIF-1α-dependent manner to disable pro-leukemogenic pathways, re-program meta2024-01-01T00:00:00Z2024 Jun2026-06-01T21:25:35.499Z2025-04-04T21:22:17.181ZS-EPMC112081593863765710.1038/s43018-024-00761-w