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

## TL;DR

The JAK2V617F mutation in myeloproliferative neoplasms changes how HIF-1 functions, leading to disease-specific gene activation and worse patient outcomes.

## Contribution

This study reveals a non-canonical HIF-1 regulon in JAK2V617F-driven cancers, linking it to disease severity and PIM1 kinase.

## Key findings

- JAK2V617F stabilizes HIF-1α in normal oxygen conditions, activating a distinct gene set.
- The JAK2V617F-HIF-1 regulon is associated with disease severity and patient survival in MPNs.
- PIM1 kinase mediates HIF-1α stabilization in JAK2V617F-MPNs, altering HIF-1 transcriptional function.

## 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.