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Whilst malignant context directs the role of HIFs within oncogenesis, these mechanisms are not well characterised. Applying the JAK2V617F myeloproliferative neoplasms (MPNs) oncogene-driver model, in which HIF-1\u03b1 is stabilised in normoxia (20% O\n                    <jats:sub>2<\/jats:sub>\n                    ), we sought to determine whether the modality of HIF-1 activation directs its function. Through direct analysis of hypoxia-activated vs. JAK2V617F-activated HIF-1 at the chromatin, we define a JAK2V617F-HIF-1 regulon that diverges from canonical HIF\/hypoxia targets. In a cohort of 172 JAK2V617F-MPN patients, we observe significant association of the JAK2V617F-HIF-1 regulon, but not canonical HIF-1 gene signatures, with disease severity, progression, and patient survival. We further define a subset gene signature (HIF1-MPN-BP) significantly associated with spontaneous transformation to blast phase MPNs. Finally, we identify that JAK2V617F-induced HIF-1\u03b1 stabilisation is mediated via PIM1 kinase. Our findings demonstrate that HIF-1 activation by the JAK2V617F-PIM1 axis significantly alters HIF-1 transcription function, desensitising HIF-1 activity to cellular oxygen levels, and restricting the HIF-1 regulon to a set of disease-associated target genes within JAK2V617F-MPNs. These findings restore the potential for specific therapeutic targeting of HIF-1 by delineating malignant activation from the physiological hypoxic response.\n                  <\/jats:p>","DOI":"10.1038\/s41375-025-02843-9","type":"journal-article","created":{"date-parts":[[2026,2,2]],"date-time":"2026-02-02T09:11:20Z","timestamp":1770023480000},"page":"609-621","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["JAK2V617F reprograms Hypoxia Inducible Factor-1 to induce a non-canonical hypoxia regulon in myeloproliferative neoplasms"],"prefix":"10.1038","volume":"40","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9246-8134","authenticated-orcid":false,"given":"David","family":"Kealy","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7978-9873","authenticated-orcid":false,"given":"Ruth","family":"Ellerington","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4023-6635","authenticated-orcid":false,"given":"Suraj","family":"Bansal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6597-4613","authenticated-orcid":false,"given":"Jessie J. 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CAH is a co-founder and shareholder of Antigonie Biosciences. ISH receives research funding from Incyte Corporation. BP is a co-founder and major shareholder of Alethiomics; has received honoraria for speaking engagements and\/or advisory work for Incyte, BMS, Constellation Therapeutics, GSK, Blueprint Medicines, Novartis, and Alethiomics; and has received research funding from Incyte, Galecto, and Alethiomics. VG reports consultancy with AbbVie, Bristol Myers Squibb\/Celgene, Novartis, Pfizer, Daiichi Sankyo, GSK, Incyte; data safety or advisory board participation with AbbVie, Bristol Myers Squibb\/Celgene, GSK, Incyte; honoraria from Bristol Myers Squibb\/Celgene, Novartis; research support from Novartis, AbbVie. JED has licensing agreements with Trillium Therapeutics and Pfizer for SIRP-a and has a sponsored research agreement with BMS. KSB is a co-founder and major shareholder of Antigonie Biosciences. JED reports receiving a commercial research grant from Celgene\/BMS and has patents licensed to Trillium Therapeutics\/Pfizer.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}},{"value":"All methods described in this manuscript were performed in accordance with the relevant guidelines and regulations. 172 JAK2V617F positive patients included in this study were part of a 358-patient study [\n                      \n                      ] identified from the MPN registry at the Princess Margaret Cancer Centre (ClinicalTrials.gov Identifier: NCT02760238), from whom peripheral blood mononuclear cells (PB-MNCs) were collected at the first visit to Princess Margaret. Inclusion criteria consisted of a diagnosis of MF, including PMF, pre-fibrotic MF, post-ET MF, or post-PV MF in chronic phase. Individuals were excluded if they received a diagnosis of MPN-Unclassified (MPN-U), MPN\/myelodysplastic syndrome (MDS) overlap, or lacked a biospecimen. All biological samples were collected under Research Ethics Board approval (REB#17-5601) with written informed consent as per the Declaration of Helsinki and were viably frozen in the Princess Margaret, hematologic malignancies tissue bank.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}}]}}