Abstract

The discovery of the activating Janus kinase (JAK)2V617F mutation in 2005 in most patients with the classic Philadelphia chromosome-negative myeloproliferative neoplasms (MPN) spurred intense interest in research into these disorders, culminating in the identification of activating mutations in MPL in 2006 and indels in the gene encoding calreticulin (CALR) in 2013, thus providing additional mechanistic explanations for the universal activation of JAK-signal transducer and activator of transcription (JAK-STAT) observed in these conditions, and the success of the JAK1/2 inhibitor ruxolitinib, which first received regulatory approval in 2011. The field has continued to advance rapidly since then, and the past 2 years have witnessed important changes to the classification of MPN and diagnostic criteria for polycythemia vera (PV), novel insights into the mechanisms of bone marrow fibrosis in primary myelofibrosis (PMF), increasing appreciation of the biologic differences between essential thrombocythemia (ET), prefibrotic and overt PMF, and between primary and post-PV/ET myelofibrosis (MF). Additionally, the mechanisms through which mutant CALR drives JAK-STAT pathway activation and oncogenic transformation are now better understood. Although mastocytosis is no longer included under the broad heading of MPN in the 2016 revision to the World Health Organization classification, an important milestone in mastocytosis research was reached in 2017 with the regulatory approval of midostaurin for patients with advanced systemic mastocytosis (AdvSM). In this article, we review the major recent developments in the areas of PV, ET, and MF, and also briefly summarize the literature on midostaurin and other KIT inhibitors for patients with AdvSM.

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