Overactive JAK pathway signaling is a key mechanism of disease in the myeloproliferative neoplasms (MPNs) polycythemia vera and myelofibrosis.1,2
Signaling of the JAK pathway plays a key role in normal cell functioning.3-6 Well-regulated JAK signaling is essential for cell production, cell proliferation, and immune function. Intracellular regulators, such as suppressor of cytokine signaling (SOCS), help regulate JAK signaling.3,4
Cytokines bind to receptors and activate JAKs. JAKs activate signal transducers and activators of transcription (STATs), which dimerize and enter the nucleus. Inside the nucleus, the STATs bind to DNA, stimulating the expression of genes related to cell survival, differentiation, and proliferation.4,7-9
The complex JAK pathway may become overactivated by many mechanisms.3,10-17 Somatic mutations primarily involve JAK2, CALR, or MPL.3,10-17 Approximately 90% of patients with myelofibrosis carry one of these mutations.18 Approximately 95% of patients with polycythemia vera have the JAK2 V617F mutation.1 Other mechanisms may include increased JAK1 signaling, an excess of cytokines activating the receptors, or impaired intracellular regulators such as SOCS.3,10-17
Ruxolitinib, a kinase inhibitor, inhibits Janus-associated kinases 1 and 2 (JAK1 and JAK2), which mediate the signaling of a number of cytokines and growth factors that are important for hematopoiesis and immune function.19
In a mouse model of JAK2 V617F–positive MPN, oral administration of ruxolitinib19:
Ruxolitinib is indicated for treatment of patients with polycythemia vera who have had an inadequate response to or are intolerant of hydroxyurea.
Ruxolitinib is indicated for treatment of patients with intermediate or high-risk myelofibrosis, including primary myelofibrosis, post-polycythemia vera myelofibrosis, and post-essential thrombocythemia myelofibrosis.