A Broad Overview of Signaling in Ph-Negative Classic Myeloproliferative Neoplasms

SIMPLE SUMMARY: There is growing evidence that Ph-negative myeloproliferative neoplasms are disorders in which multiple signaling pathways are significantly disturbed. The heterogeneous phenotypes observed among patients have highlighted the importance of having a comprehensive knowledge of the molecular mechanisms behind these diseases. This review aims to show a broad overview of the signaling involved in myeloproliferative neoplasms (MPNs) and other processes that can modify them, which could be helpful to better understand these diseases and develop more effective targeted treatments. ABSTRACT: Ph-negative myeloproliferative neoplasms (polycythemia vera (PV), essential thrombocythemia (ET) and primary myelofibrosis (PMF)) are infrequent blood cancers characterized by signaling aberrations. Shortly after the discovery of the somatic mutations in JAK2, MPL, and CALR that cause these diseases, researchers extensively studied the aberrant functions of their mutant products. In all three cases, the main pathogenic mechanism appears to be the constitutive activation of JAK2/STAT signaling and JAK2-related pathways (MAPK/ERK, PI3K/AKT). However, some other non-canonical aberrant mechanisms derived from mutant JAK2 and CALR have also been described. Moreover, additional somatic mutations have been identified in other genes that affect epigenetic regulation, tumor suppression, transcription regulation, splicing and other signaling pathways, leading to the modification of some disease features and adding a layer of complexity to their molecular pathogenesis. All of these factors have highlighted the wide variety of cellular processes and pathways involved in the pathogenesis of MPNs. This review presents an overview of the complex signaling behind these diseases which could explain, at least in part, their phenotypic heterogeneity.