Inflammatory mediators differentially regulate megakaryopoiesis and thrombopoiesis in myelofibrosis and essential thrombocythemia

Abstract

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