Janus kinase 2 (JAK2) V617F mutant (JAK2-V617F)

Janus kinase 2 (JAK2) V617F is a somatic gain-of-function mutation characterized by a valine-to-phenylalanine substitution at position 617 in the JH2 pseudokinase domain of the JAK2 enzyme [1, 4]. This mutation disrupts the normal auto-inhibitory function of the JH2 domain, leading to constitutive activation of the JAK-STAT signaling pathway independent of cytokine stimulation [5, 13]. It is the primary driver in Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs), occurring in approximately 95% of patients with polycythemia vera and 50-60% of those with essential thrombocythemia or primary myelofibrosis [6, 14]. Therapeutic intervention primarily utilizes small-molecule JAK inhibitors, such as ruxolitinib and fedratinib, which compete for the ATP-binding site in the kinase domain to reduce myeloproliferation and inflammatory cytokine production [1, 9]. While these drugs effectively manage symptoms and splenomegaly, they often lack selectivity for the mutant protein over wild-type JAK2, leading to dose-limiting cytopenias [3, 12]. Current drug development efforts are focused on next-generation allosteric inhibitors that specifically target the mutated JH2 domain to achieve disease modification and reduce off-target toxicity [3, 12].

Other names

JAK2 V617FJanus kinase 2 Val617PheJAK2V617FJAK2 exon 14 mutationJanus kinase 2 V617F mutation

ATP-competitive inhibition of the JAK2 kinase domain (JH1) or allosteric inhibition of the pseudokinase domain (JH2)