New JAK2 inhibitors for myeloproliferative neoplasms

The discovery of the JAK(V617F) kinase established a common pathogenetic link to the most important types of Philadelphia-chromosome-negative myeloproliferative neoplasms (MPNs): polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). More importantly, the demonstration of constitutive kinase activity emanating from the JAK2 protein provided the rationale for the development of small-molecule JAK2 kinase inhibitors.

Several JAK2 kinase inhibitors are being tested in clinical trials for patients with MPNs. In PMF trials, JAK2 inhibitors have been shown to produce rapid reductions in spleen size and marked improvements in constitutional symptoms and quality of life. In ET and/or PV, JAK2 inhibitors normalize hematocrit, platelets and WBC, and spleen size in a large number of patients that are resistant or intolerant to hydroxyurea. JAK2 inhibitors are not specific for the JAK2V617F mutant protein. Rather, they inhibit the JAK2- signal transducer and activator of transcription (STAT) pathway and therefore any patient with MPN may benefit from therapy regardless of JAK2 mutational status.

JAK2 inhibitors induce clinically relevant responses in a large proportion of patients with MPNs. Because JAK kinase activation underlies the pathogenesis of other disorders, such as autoimmune and rheumatological disorders, the paradigm of JAK inhibition may translate into novel therapies for a variety of human diseases.