dc.contributor.author | Lawson, H | |
dc.contributor.author | Holt-Martyn, JP | |
dc.contributor.author | Dembitz, V | |
dc.contributor.author | Kabayama, Y | |
dc.contributor.author | Wang, LM | |
dc.contributor.author | Bellani, A | |
dc.contributor.author | Atwal, S | |
dc.contributor.author | Saffoon, N | |
dc.contributor.author | Durko, J | |
dc.contributor.author | van de Lagemaat, LN | |
dc.contributor.author | De Pace, AL | |
dc.contributor.author | Tumber, A | |
dc.contributor.author | Corner, T | |
dc.contributor.author | Salah, E | |
dc.contributor.author | Arndt, C | |
dc.contributor.author | Brewitz, L | |
dc.contributor.author | Bowen, M | |
dc.contributor.author | Dubusse, L | |
dc.contributor.author | George, D | |
dc.contributor.author | Allen, L | |
dc.contributor.author | Guitart, AV | |
dc.contributor.author | Fung, TK | |
dc.contributor.author | So, CWE | |
dc.contributor.author | Schwaller, J | |
dc.contributor.author | Gallipoli, P | |
dc.contributor.author | O'Carroll, D | |
dc.contributor.author | Schofield, CJ | |
dc.contributor.author | Kranc, KR | |
dc.coverage.spatial | England | |
dc.date.accessioned | 2024-07-04T13:54:02Z | |
dc.date.available | 2024-07-04T13:54:02Z | |
dc.date.issued | 2024-06-01 | |
dc.identifier | 10.1038/s43018-024-00761-w | |
dc.identifier.citation | Nature Cancer, 2024, 5 (6), pp. 916 - 937 | en_US |
dc.identifier.issn | 2662-1347 | |
dc.identifier.uri | https://repository.icr.ac.uk/handle/internal/6300 | |
dc.identifier.eissn | 2662-1347 | |
dc.identifier.eissn | 2662-1347 | |
dc.identifier.doi | 10.1038/s43018-024-00761-w | |
dc.identifier.doi | 10.1038/s43018-024-00761-w | |
dc.description.abstract | 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 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-1α stabilization, is a promising nontoxic strategy for AML, including in combination with venetoclax. | |
dc.format | Print-Electronic | |
dc.format.extent | 916 - 937 | |
dc.language | eng | |
dc.language.iso | eng | en_US |
dc.publisher | NATURE PORTFOLIO | en_US |
dc.relation.ispartof | Nature Cancer | |
dc.rights.uri | http://creativecommons.org/licenses/by/4.0/ | en_US |
dc.subject | Leukemia, Myeloid, Acute | |
dc.subject | Hypoxia-Inducible Factor 1, alpha Subunit | |
dc.subject | Humans | |
dc.subject | Hypoxia-Inducible Factor-Proline Dioxygenases | |
dc.subject | Prolyl-Hydroxylase Inhibitors | |
dc.subject | Animals | |
dc.subject | Mice | |
dc.subject | Disease Progression | |
dc.subject | Apoptosis | |
dc.subject | Proto-Oncogene Proteins | |
dc.subject | Membrane Proteins | |
dc.subject | Cell Line, Tumor | |
dc.subject | Sulfonamides | |
dc.subject | Proto-Oncogene Proteins c-bcl-2 | |
dc.subject | Protein Stability | |
dc.subject | Bridged Bicyclo Compounds, Heterocyclic | |
dc.title | The selective prolyl hydroxylase inhibitor IOX5 stabilizes HIF-1α and compromises development and progression of acute myeloid leukemia. | en_US |
dc.type | Journal Article | |
dcterms.dateAccepted | 2024-03-15 | |
dc.date.updated | 2024-07-04T13:53:30Z | |
rioxxterms.version | VoR | en_US |
rioxxterms.versionofrecord | 10.1038/s43018-024-00761-w | en_US |
rioxxterms.licenseref.startdate | 2024-06-01 | |
rioxxterms.type | Journal Article/Review | en_US |
pubs.author-url | https://www.ncbi.nlm.nih.gov/pubmed/38637657 | |
pubs.issue | 6 | |
pubs.organisational-group | ICR | |
pubs.publication-status | Published | |
pubs.publisher-url | http://dx.doi.org/10.1038/s43018-024-00761-w | |
pubs.volume | 5 | |
icr.researchteam | Haemato-Oncology | en_US |
dc.contributor.icrauthor | Kranc, Kamil | |
icr.provenance | Deposited by Mr Arek Surman on 2024-07-04. Deposit type is initial. No. of files: 1. Files: s43018-024-00761-w.pdf | |