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

Janus kinase 2 (JAK2) V617F is a somatic point mutation in the JAK2 gene, characterized by a G to T transversion at nucleotide 1849, which results in a valine to phenylalanine substitution at codon 617 [1, 15]. This mutation is located within the JH2 pseudokinase domain, which typically exerts an inhibitory effect on the JH1 catalytic kinase domain; the V617F substitution disrupts this autoinhibition, leading to constitutive activation of the JAK2 protein [1, 2, 12]. This hyperactivation triggers the JAK-STAT signaling pathway, driving the uncontrolled proliferation of hematopoietic stem cells and the overproduction of blood cells [4, 8, 10]. It is the primary genetic driver in BCR-ABL1-negative myeloproliferative neoplasms (MPNs), including polycythemia vera (where it is present in ~95% of cases), essential thrombocythemia (~50-60%), and primary myelofibrosis (~50-60%) [5, 9, 15]. Current therapeutic strategies utilize small-molecule JAK inhibitors like ruxolitinib and fedratinib to block kinase activity and alleviate symptoms, though these often lack mutant-specificity and can cause cytopenias by inhibiting wild-type JAK2 [2, 3, 5]. Advanced research is exploring mutant-selective allosteric inhibitors and CRISPR/Cas9-based gene editing to specifically target the V617F DNA sequence or the mutated JH2 domain to achieve disease modification [3, 13, 14].

Other names

JAK2 Val617PheJanus kinase 2 V617F mutationJAK2 V617F variantJAK2 p.V617F

Inhibition of the JAK2 kinase domain (JH1) or allosteric targeting of the JH2 pseudokinase domain to suppress constitutive JAK-STAT signaling.