Janus kinase 2 (V617F mutant) (JAK2 V617F)

Janus kinase 2 (JAK2) is a non-receptor tyrosine kinase that is essential for the signaling of various cytokine receptors, including those for erythropoietin, thrombopoietin, and granulocyte colony-stimulating factor (Source: UniProt P23458). The V617F mutation is a somatic point mutation occurring in exon 14 of the JAK2 gene, where a guanine is substituted by thymine, resulting in a valine-to-phenylalanine change at position 617 (Source: PubMed PMID: 15752423). This mutation occurs in the JH2 pseudokinase domain, which normally exerts an inhibitory effect on the JH1 kinase domain; the mutation relieves this inhibition, leading to constitutive activation of the JAK-STAT signaling pathway (Source: NIH/NCI). This hyperactivation drives the uncontrolled proliferation of myeloid cells, serving as a primary driver for Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs), such as polycythemia vera, essential thrombocythemia, and primary myelofibrosis (Source: StatPearls). Therapeutic intervention typically involves small-molecule JAK inhibitors, such as ruxolitinib and fedratinib, which compete with ATP at the kinase domain to dampen signaling (Source: FDA). While effective at reducing splenomegaly and systemic symptoms, these drugs often target both mutant and wild-type JAK2, leading to common side effects like anemia and thrombocytopenia (Source: Mayo Clinic). Monitoring the JAK2 V617F allele burden is a critical biomarker for diagnosis and assessing treatment response in patients with these disorders (Source: Leukemia & Lymphoma Society).

Other names

JAK2 V617FJanus kinase 2 Val617PheJAK2*V617FJAK2 exon 14 mutationJAK2 V617F mutant allele

ATP-competitive inhibition of the Janus kinase 2 (JAK2) catalytic domain, preventing the phosphorylation of STAT proteins and reducing downstream pro-proliferative gene expression.