JAK2V617F reprograms Hypoxia Inducible Factor-1 to induce a non-canonical hypoxia regulon in myeloproliferative neoplasms

David Kealy; Ruth Ellerington; Suraj Bansal; Jessie J.F. Medeiros; Catherine A. Hawley; Andy G.X. Zeng; Jakub Lukaszonek; Katie A. West; Aparna D. Sinha; Gillian Caalim; Richard T. Gawne; Jacob Pope; Bianca Lima Ferreira; Nicole Mae Blacknell; Bryce Drylie; Jenny Chatzigerou; Hwei Minn Khoo; Adam C. Wilkinson; Adele K. Fielding; Guanlin Wang; Bethan Psaila; David G. Kent; Ian S. Hitchcock; Andrew N. Holding; Andrew S. Mason; Vikas Gupta; John E. Dick; Katherine S. Bridge

doi:10.1038/s41375-025-02843-9

JAK2V617F reprograms Hypoxia Inducible Factor-1 to induce a non-canonical hypoxia regulon in myeloproliferative neoplasms

David Kealy, Ruth Ellerington, Suraj Bansal, Jessie J.F. Medeiros, Catherine A. Hawley, Andy G.X. Zeng, Jakub Lukaszonek, Katie A. West, Aparna D. Sinha, Gillian Caalim, Richard T. Gawne, Jacob Pope, Bianca Lima Ferreira, Nicole Mae Blacknell, Bryce Drylie, Jenny Chatzigerou, Hwei Minn Khoo, Adam C. Wilkinson, Adele K. Fielding, Guanlin WangBethan Psaila, David G. Kent, Ian S. Hitchcock, Andrew N. Holding, Andrew S. Mason, Vikas Gupta, John E. Dick, Katherine S. Bridge^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

Abstract

Hypoxia-inducible factors (HIFs) are master transcriptional regulators, central to cellular survival in hypoxia and frequently activated within malignancy. 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-1α is stabilised in normoxia (20% O₂), 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-1α 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. (Figure presented.)

Original language	English
Number of pages	13
Journal	Leukemia
Early online date	2 Feb 2026
DOIs	https://doi.org/10.1038/s41375-025-02843-9
Publication status	E-pub ahead of print - 2 Feb 2026

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© The Author(s) 2026.

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JAK2V617F reprograms Hypoxia Inducible Factor-1 to induce a non-canonical hypoxia regulon in myeloproliferative neoplasms.
© The Author(s) 2026
Final published version, 4.83 MBLicence: CC BY

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Kealy, D., Ellerington, R., Bansal, S., Medeiros, J. J. F., Hawley, C. A., Zeng, A. G. X., Lukaszonek, J., West, K. A., Sinha, A. D., Caalim, G., Gawne, R. T., Pope, J., Ferreira, B. L., Blacknell, N. M., Drylie, B., Chatzigerou, J., Khoo, H. M., Wilkinson, A. C., Fielding, A. K., ... Bridge, K. S. (2026). JAK2V617F reprograms Hypoxia Inducible Factor-1 to induce a non-canonical hypoxia regulon in myeloproliferative neoplasms. Leukemia. Advance online publication. https://doi.org/10.1038/s41375-025-02843-9

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title = "JAK2V617F reprograms Hypoxia Inducible Factor-1 to induce a non-canonical hypoxia regulon in myeloproliferative neoplasms",

abstract = "Hypoxia-inducible factors (HIFs) are master transcriptional regulators, central to cellular survival in hypoxia and frequently activated within malignancy. 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-1α is stabilised in normoxia (20% O2), 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-1α 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. (Figure presented.)",

author = "David Kealy and Ruth Ellerington and Suraj Bansal and Medeiros, {Jessie J.F.} and Hawley, {Catherine A.} and Zeng, {Andy G.X.} and Jakub Lukaszonek and West, {Katie A.} and Sinha, {Aparna D.} and Gillian Caalim and Gawne, {Richard T.} and Jacob Pope and Ferreira, {Bianca Lima} and Blacknell, {Nicole Mae} and Bryce Drylie and Jenny Chatzigerou and Khoo, {Hwei Minn} and Wilkinson, {Adam C.} and Fielding, {Adele K.} and Guanlin Wang and Bethan Psaila and Kent, {David G.} and Hitchcock, {Ian S.} and Holding, {Andrew N.} and Mason, {Andrew S.} and Vikas Gupta and Dick, {John E.} and Bridge, {Katherine S.}",

note = "Publisher Copyright: {\textcopyright} The Author(s) 2026.",

year = "2026",

month = feb,

day = "2",

doi = "10.1038/s41375-025-02843-9",

language = "English",

journal = "Leukemia",

issn = "0887-6924",

}

Kealy, D, Ellerington, R, Bansal, S, Medeiros, JJF, Hawley, CA, Zeng, AGX, Lukaszonek, J, West, KA, Sinha, AD, Caalim, G, Gawne, RT, Pope, J, Ferreira, BL, Blacknell, NM, Drylie, B, Chatzigerou, J, Khoo, HM, Wilkinson, AC, Fielding, AK, Wang, G, Psaila, B, Kent, DG , Hitchcock, IS , Holding, AN , Mason, AS, Gupta, V, Dick, JE & Bridge, KS 2026, 'JAK2V617F reprograms Hypoxia Inducible Factor-1 to induce a non-canonical hypoxia regulon in myeloproliferative neoplasms', Leukemia. https://doi.org/10.1038/s41375-025-02843-9

TY - JOUR

T1 - JAK2V617F reprograms Hypoxia Inducible Factor-1 to induce a non-canonical hypoxia regulon in myeloproliferative neoplasms

AU - Kealy, David

AU - Ellerington, Ruth

AU - Bansal, Suraj

AU - Medeiros, Jessie J.F.

AU - Hawley, Catherine A.

AU - Zeng, Andy G.X.

AU - Lukaszonek, Jakub

AU - West, Katie A.

AU - Sinha, Aparna D.

AU - Caalim, Gillian

AU - Gawne, Richard T.

AU - Pope, Jacob

AU - Ferreira, Bianca Lima

AU - Blacknell, Nicole Mae

AU - Drylie, Bryce

AU - Chatzigerou, Jenny

AU - Khoo, Hwei Minn

AU - Wilkinson, Adam C.

AU - Fielding, Adele K.

AU - Wang, Guanlin

AU - Psaila, Bethan

AU - Kent, David G.

AU - Hitchcock, Ian S.

AU - Holding, Andrew N.

AU - Mason, Andrew S.

AU - Gupta, Vikas

AU - Dick, John E.

AU - Bridge, Katherine S.

PY - 2026/2/2

Y1 - 2026/2/2

N2 - Hypoxia-inducible factors (HIFs) are master transcriptional regulators, central to cellular survival in hypoxia and frequently activated within malignancy. 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-1α is stabilised in normoxia (20% O2), 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-1α 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. (Figure presented.)

AB - Hypoxia-inducible factors (HIFs) are master transcriptional regulators, central to cellular survival in hypoxia and frequently activated within malignancy. 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-1α is stabilised in normoxia (20% O2), 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-1α 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. (Figure presented.)

UR - http://www.scopus.com/inward/record.url?scp=105029245383&partnerID=8YFLogxK

U2 - 10.1038/s41375-025-02843-9

DO - 10.1038/s41375-025-02843-9

M3 - Article

AN - SCOPUS:105029245383

SN - 0887-6924

JO - Leukemia

JF - Leukemia

ER -

JAK2V617F reprograms Hypoxia Inducible Factor-1 to induce a non-canonical hypoxia regulon in myeloproliferative neoplasms

Abstract

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