Finding NEMO

This project aims to investigate the immune-modulation mechanisms involved in inflammation and pharmacological response following JAK/STAT pathway activation, with a focus on myelofibrosis (MF), a Philadelphia-negative chronic myeloproliferative neoplasm. In MF, a gain-of-function mutation in JAK2 — found in over 50% of patients — leads to uncontrolled megakaryocyte proliferation, bone marrow fibrosis, cytopenia, and extramedullary hematopoiesis. Ruxolitinib, a JAK1/2 inhibitor, has significantly improved patient outcomes by reducing inflammation and enhancing quality of life and survival; however, approximately half of MF patients fail to respond to this treatment for still unknown reasons. The hypothesis is that immune mechanisms beyond JAK/STAT activation — particularly extracellular vesicles (EVs) released into peripheral blood — may drive hyperinflammation. EVs, through their cargo including miRNAs and bioactive sphingolipids, modulate immune responses and may influence both response and resistance to Ruxolitinib. Using a multistep approach combining MF patient samples and zebrafish embryos, these mechanisms will be investigated before and after treatment. The findings are expected to have broader relevance, as the hyperinflammatory state of MF resembles that of rheumatoid arthritis, neurological and cardiovascular diseases, graft-versus-host disease, and viral infections such as SARS-CoV-2. Finally, EVs could serve as host-based prognostic biomarkers to guide clinical treatment decisions in hyperinflamed patients.