PhD defence J.E. (Jess) Pritchard

Below is a brief summary of the dissertation:

This research highlights the complex, cell type specific roles of hedgehog signaling as well as its links to inflammation in the development of Myeloproliferative Neoplasm (MPN). We show that in hematopoietic cells, the GLI1 transcription factor is activated via non-canonical, inflammation linked pathways, promoting clonal expansion and further inflammatory cytokine secretion driving critical disease phenotype. Additionally, we describe how in non-hematopoietic stromal cells, canonical GLI2 activation drives fibrosis. In both cases, inflammation emerges as a central disease driving mechanism.

Targeting GLI1, GLI2, and CXCL4, effectively reduces fibrosis and inflammatory signalling, suggesting a path forward beyond the current first line treatment option of JAK inhibitor monotherapy. Our research also suggests that blocking PDGFRβ-driven inflammation could prevent disease progression and secondary malignancies.

Thus, future MPN treatment strategies should take combinatorial strategies into consideration, guided by biomarkers such as GLI1 expression and circulating inflammatory cytokines. Overall, this mechanism-based approach offers new hope for more effective, disease-modifying therapies in MPN patients.