Current outlook on molecular pathogenesis and treatment of myeloproliferative neoplasms.

Discovery of the JAK2 V617F mutation in the myeloproliferative neoplasms (MPNs) essential thrombocythemia (ET), polycythemia vera (PV), and primary myelofibrosis (PMF) has stimulated great interest in the underlying molecular mechanisms and treatment of these diseases. Along with acceleration of technologies, novel mutations in genes such as MPL, LNK, and CBL have been discovered that converge on the JAK-STAT pathway. Several additional novel mutations in genes involved in epigenetic regulation of the genome, including TET2, ASXL1, DNMT3A, and IDH1/2, have emerged, in addition to several mutations in cellular splicing machinery. While understanding of the pathogenetic mechanisms of these novel mutations in MPNs has improved, it is still lagging behind the pace of mutation discovery. Concurrent with molecular discoveries, especially with regard to JAK-STAT signaling, therapeutic development has accelerated in recent years. More than ten JAK kinase inhibitors have been advanced into clinical trials. Recently the first JAK2 inhibitor was approved for use in patients with PMF. Most JAK-targeting agents share similar characteristics with regard to clinical benefit, consisting of improvements in splenomegaly, constitutional symptoms, and cytopenias, for example. It remains to be determined if JAK2 inhibitors can considerably impact disease progression and bone marrow histologic features (e.g., fibrosis) or significantly impact the JAK2 allele burden. While JAK2 inhibitors appear to be promising in PV and ET, they need to be compared with standard therapies, such as hydroxyurea or interferon-based therapies. Future clinical development will focus on optimal combination partners and agents that target alternative mechanisms, deepen the response, and achieve molecular remissions.