The inflammatory/immune side of Myelofibrosis: a biological update

Myelofibrosis (MF) is a clonal disorders of hematopoietic stem cell. Mutations in 3 genes (JAK2, CALR, MPL) and chronic inflammation are the hallmark of MF. Infectious complications are the leading cause of morbidity and mortality. Ruxolitinib (RUX) therapy, a JAK1/2 inhibitor, suppresses both clonal myeloproliferation and release of proinflammatory cytokines, exerting also immunosuppressive activity. The main aim of my PhD project was the functional characterization of the immune/inflammatory microenvironment of MF. Specifically, we aimed: 1) to analyse the role of circulating microvesicles as disease biomarker in MF; 2) to investigate the phenotype/function of circulating monocytes in the inflammatory microenvironment of MF patients and to evaluate whether RUX may influence their behaviour. Focusing on circulating microvesicles, we demonstrated that: 1) the circulating megakaryocyte/platelet-derived microvesicles profile is altered; 2) according to IPSS score, Intermediate 2/high risk patients show respectively reduced/increased megakaryocyte/platelet-microvesicles proportion as compared with the intermediate1/low risk patients; 3) at baseline spleen-responders patients show a significantly increased megakaryocyte-microvesicles proportion as compared with the non-responder counterparts. Importantly, a cut-off value below 19.95% of megakaryocyte-microvesicles predicted RUX response. Interestingly, RUX therapy restores the normal megakaryocyte/platelet-microvesicles profile in spleen-responders patients only. On this basis, circulating megakaryocyte/platelet-microvesicles could have a diagnostic and prognostic role in MF. Finally, focusing on the immune microenvironment of JAK2V617F mutated MF patients, circulating monocytes show an altered activation/differentiation program and a reduced in vitro capacity to produce/secrete inflammatory cytokines in response to an infectious stimulus. Importantly, RUX therapy improves intracellular pro-inflammatory cytokines production of MF-monocytes and promotes the in vitro release of inflammatory cytokines associated with monocytes-derived microvesicles in response to an infectious stimulus. These findings contribute to better understand the immune biology in the setting of the MF and refines the biological effects of RUX.