Unravelling the regulation of HIF-1 by JAK-STAT signalling in mice and Drosophila myeloid neoplasia models

Myeloproliferative neoplasia (MPNs) encompasses a heterogeneous group of haematologic malignancies characterised by uncontrolled proliferation of myeloid cells. The JAK2V617F mutation (JAKVF), common in MPNs, is known to drive disease pathogenesis. Hypoxia-inducible factors (HIFs) are master transcriptional regulators of cellular responses to hypoxia. Although the context of their activation heavily affects whether they are oncogenic or tumour-suppressive, HIFs constitutive activation is often associated with MPNs. Recently, HIF-1 has been shown to be activated by PIM1, which drives progression of JAKVF MPNs; however, the mechanisms surrounding this are not well understood.
This project investigated the role of HIF-1 in JAK2V617F-positive MPN in mouse and Drosophila MPN models. In murine haematopoietic stem cell (HSC) expansion cultures, inhibitors targeting HIF-1α and PIM1 altered lineage fate by increasing long-term HSC cell proportions while decreasing multipotent progenitor populations. Both inhibitors altered myeloid progenitor populations, suggesting that targeting PIM1 and HIF has the potential to restore haematopoietic balance and holds promise for developing effective therapies.
In Drosophila, heterozygous hop mutants (hopTum-1 and hopT42), homologous to the human JAKVF mutations, exhibited increased temperature-dependent tumour burden. Overexpression of the HIF-1α homolog, Sima, in haemocytes further exacerbated tumour severity. The co-expression of Sima in blood cells and hop mutants also worsened tumour activity. Sima loss, using larger genomic deficiency fly lines, increased tumour severity when reared in hopT42 29°C conditions, potentially due to disruption of other genes.
This research demonstrates the impact of HIF-1α inhibition on murine HSC populations and the conserved interaction between HIF and JAK-STAT signalling in Drosophila MPN models, suggesting that the HIF pathway has the potential to be a therapeutically relevant target in JAK2V617F-positive MPNs. Understanding the precise mechanisms of HIF-1α within JAK2V617F-positive MPN disease cases could pave the way for the development of novel and personalised treatments that address drug resistance in MPN patients.