Janus kinase inhibitors for the treatment of myeloproliferative neoplasias and beyond

Key Points The discovery of the V617F mutation in Janus kinase 2 (JAK2) in 2005 provided, for the first time, a molecular taxonomic nexus that definitively linked the myeloproliferative neoplasms (MPNs) polycythaemia vera, essential thrombocythaemia and primary myelofibrosis. JAK2V617F is constitutively activated, and so also provides the rationale for the development of small molecular mass compounds targeted at disrupting such activity in the mutated enzyme. A growing number of JAK inhibitors are being developed for the treatment of MPNs; the JAK1 and JAK2 inhibitor ruxolitinib and the selective JAK2 inhibitor TG101348 are furthest along in clinical development, but many others are undergoing clinical testing. JAK2 inhibitors produce remarkable improvements in spleen size and constitutional symptoms of MPNs but have limited activity in improving cytopaenias, decreasing the mutant JAK2V617F allelic burden or improving marrow fibrosis. The mechanism of action of JAK inhibitors in patients with MPNs is not fully understood as responses are seen both in patients with and without the JAK2V617F mutation. Recently reported knock-in mouse models, in which JAK2V617F is expressed from the endogenous promoter, will become invaluable tools for the development of novel therapies for MPNs and for gaining further understanding of the biology of these malignancies. A series of novel mutant alleles (TET2, ASXL1, CBL, IDH1/IDH2, IKZF1, EZH2 and LNK) have been reported in the last 24 months in subsets of patients with MPNs. However, the role of these alleles in those malignancies remains to be determined. Because JAKs are involved in the pathogenesis of inflammatory and immune-mediated disorders, JAK inhibitors are also being tested in clinical trials for these indications and have shown remarkable results in rheumatoid arthritis and psoriasis as well as in prevention of allograft rejection. Activating mutations in Janus kinase 2 (JAK2) are a common feature of a number of myeloproliferative neoplasms. JAKs are also involved in the pathogenesis of inflammatory and immune-mediated disorders, and several JAK inhibitors are now in clinical development. In this Review, Quintás-Cardama and colleagues discuss the current progress in this field. Recent advances in our understanding of the pathogenesis of the Philadelphia chromosome-negative myeloproliferative neoplasms, polycythaemia vera, essential thrombocythaemia and myelofibrosis have led to the identification of the mutation