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Chronic myeloproliferative neoplasms are characterized by clonal myeloid expansion driven by activating mutations in the JAK2 pathway and chronic inflammation. The aim was to investigate the contribution of circulating inflammatory mediators to the abnormalities in the megakaryocytic lineage characteristic of MF and ET. Plasma samples from 30 MF and 28 ET patients were incubated with normal cord-blood CD34 + progenitors and megakaryo/thrombopoiesis was evaluated. MF plasma increased megakaryocyte output, which was attenuated in sequential samples from ruxolitinib-treated patients. JAK1/2, MAPK and NF-kB inhibitors reverted this effect, revealing the concomitant involvement of all three pathways. Elevated levels of circulating IL-1β and IL-6 correlated with megakaryocyte output, which was reverted by blocking antibodies, indicating this phenotype is partly driven by these inflammatory cytokines. Instead, ET plasma promoted enhanced proplatelet formation, which was coupled with increased NFE2 and Bcl-xL expression. Elevated levels of circulating RANTES correlated with ET plasma-induced proplatelet formation, which was partially reverted by RANTES receptor CCR5 antagonist Maraviroc, indicating RANTES is involved in this process. These findings indicate that, in addition to clonal mutations, extrinsic inflammatory mediators play a direct role in MF and ET megakaryocyte abnormalities. The distinct cytokine profile could potentially be useful for the development of targeted therapies.