Disordered signaling in myeloproliferative neoplasms

The human myeloproliferative neoplasms (MPN) have long been associated with abnormal responses to cytokines and activation of signaling pathways, although the exact molecular mechanisms underlying these observations were unknown. This situation altered with the discovery of the JAK2 V617F, which presaged the ongoing description of further mutations predicted to activate canonical signaling pathways in MPN. This article covers the nature of these mutations and summarizes functional experiments in model systems and in human MPN cells to define the signaling pathways altered and how these drive and determine the MPN cellular phenotype. Also discussed are recently described, novel noncanonical signaling pathways to chromatin predicted to alter gene transcription more directly and to also contribute to the MPN phenotype.