2026-10-13T02:13:39Z https://api.figshare.com/v2/oai

oai:figshare.com:article/32805854 2026-10-01T16:12:25Z portal_1172 item_type_8 month_year_10_2026

From pathogenesis to therapy: understanding molecular drivers and novel treatments in mastocytosis and myeloproliferative neoplasms Gabrielle Moore (23158040) PUREID: 689745054 Systemic mastocytosis myeloproliferative neoplasms proteomics LC-MS/MS bioorthogonal non-canonical amino acid tagging (BONCAT) ruxolitinib Myeloproliferative neoplasms (MPNs) and systemic mastocytosis (SM) are clonal haematological disorders that originate from dysregulated haematopoietic stem cells within the bone marrow (BM). Both disorders are characterised by activating kinase mutations, <i>JAK2 V617F</i> in MPNs and <i>KIT D816V</i> in SM, and aberrant activation of these tyrosine kinases drives constitutive proliferative signalling. Persistence and suboptimal response to targeted therapies remain major clinical challenges in Philadelphia-negative MPNs. Although Janus kinase (JAK) inhibitors such as ruxolitinib (RUX) represent standard-of-care treatment for advanced MPNs, they do not fully eradicate mutant clones, prevent disease progression or reliably overcome acquired persistence. Similarly, therapeutic strategies in SM predominantly target KIT mutations, yet alternative signalling pathways may drive disease maintenance and progression. This study aimed to identify treatment-responsive signalling pathways and alternative therapeutic vulnerabilities in MPN and SM using integrated proteomic approaches. 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> 2026-10-01T16:12:25Z Text Thesis 10.17034/32805854.v1 https://figshare.com/articles/thesis/From_pathogenesis_to_therapy_understanding_molecular_drivers_and_novel_treatments_in_mastocytosis_and_myeloproliferative_neoplasms/32805854 All Rights Reserved Open Access after 2031-07-31