From pathogenesis to therapy: understanding molecular drivers and novel treatments in mastocytosis and myeloproliferative neoplasms

In MPN models, a proteasome inhibitor showed strong anti-proliferative activity. Proteosome inhibition combined with RUX showed synergistic activity and reduced the effective IC50 of RUX, supporting dual targeting as a means to enhance efficacy. A RUX-persistent essential thrombocythaemia (ET) model was generated to reflect reduced responsiveness after prolonged exposure, and persistent cells retained proteosome sensitivity similar to RUX-naïve cells.

To capture early adaptation to JAK2 inhibition, bioorthogonal non-canonical amino acid tagging (BONCAT) was implemented for the first time in an MPN cell model, enabling selective enrichment of newly synthesised proteins. Functional enrichment analysis showed time-dependent protein remodelling, with early suppression of immune-associated proteins followed by later enrichment of apoptotic and immune processes at 24 hours, providing a temporal framework for early adaptation to JAK inhibition.

In SM, global plasma proteomics identified CXCL7, LBP, TGFβ1 and PDGFRβ as candidate biomarkers. Proteomic profiling was extended to SM BM, generating a high-resolution digital proteomic map and highlighting dysregulated immune signalling. In human mast cell models, proteosome inhibition induced proteomic signatures of stress responses and apoptosis.

Overall, this work defines early proteomic responses to JAK2 inhibition and supports proteasome inhibition as a shared therapeutic vulnerability across MPN and SM models, providing a rationale for combination and pathway-diversified strategies beyond current kinase-directed therapy.<br><br><i>Thesis is embargoed until 31 July 2031</i>.<br>