Janus kinase 2 V617F (JAK2 V617F) (JAK2 V617F)

Janus kinase 2 (JAK2) V617F is a somatic point mutation located in the JH2 pseudokinase domain of the JAK2 non-receptor tyrosine kinase [UniProt: P23458]. This specific mutation involves a valine-to-phenylalanine substitution at position 617, which relieves the inhibitory effect of the JH2 domain on the JH1 catalytic domain, resulting in constitutive kinase activity [PubMed: 15752413]. It is the primary driver mutation in Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs), found in approximately 95% of patients with polycythemia vera and 50-60% of those with essential thrombocythemia or primary myelofibrosis [StatPearls: NBK482133]. The resulting hyperactivation of the JAK-STAT pathway drives the uncontrolled proliferation of hematopoietic stem cells and their progeny. Therapeutic strategies focus on small-molecule JAK inhibitors, such as ruxolitinib and fedratinib, which compete for the ATP-binding site of the kinase domain to reduce signaling [NCBI: PMC4864611]. While these agents are effective at controlling splenomegaly and systemic symptoms, they are not mutation-specific and can cause off-target suppression of normal hematopoiesis. Monitoring the JAK2 V617F allele burden is often used as a biomarker for disease progression and response to therapy.

Other names

JAK2 Val617PheJAK2V617FJanus kinase 2 (V617F)JAK2 mutation

ATP-competitive inhibition of the Janus kinase 2 tyrosine kinase domain, which prevents the phosphorylation of Signal Transducers and Activators of Transcription (STAT) proteins and suppresses downstream pro-proliferative signaling [PubMed: 21862044].