In particular, the genetic landscape of classical myeloproliferative neoplasms (MPNs) has been in large part completed with the identification of driver mutations (targeting the cytokine receptor/Janus-activated kinase 2 (JAK2) pathway) that determine MPN phenotype, as well as additional mutations mainly affecting the regulation of gene expression (epigenetics or splicing regulators) and signaling.
In >95% of cases, mutations that drive the development of an MPN phenotype occur in a mutually exclusive manner in 1 of 3 genes: <i>JAK2</i>, <i>CALR</i>, or <i>MPL</i> The thrombopoietin receptor, MPL, is the key cytokine receptor in MPN development, and these mutations all activate MPL-JAK-STAT signaling in MPN stem cells.
Based on the recent findings, this review summarizes a novel molecular mechanism by which this mutant molecular chaperone constitutively activates the cytokine receptor to induce cellular transformation in MPNs.