Abstract
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.
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.