V617F

V617F refers to a specific somatic activating mutation in the JAK2 gene, in which valine is substituted by phenylalanine at amino acid position 617. This change causes constitutive activation of the JAK-STAT signaling pathway, promoting uncontrolled proliferation of hematopoietic cells.

The mutation is most closely associated with myeloproliferative neoplasms. It is found in a large majority of polycythemia vera patients (roughly 95% or more), and in about 50–60% of essential thrombocythemia and primary myelofibrosis cases. A subset of polycythemia vera patients harbor JAK2 exon 12 mutations instead of V617F. V617F is typically absent in reactive erythrocytosis or other non-malignant conditions.

Pathophysiology and clinical features: JAK2 V617F drives clonal expansion of erythroid, megakaryocytic, and granulocytic lineages, contributing to erythrocytosis, thrombocytosis, or leukocytosis, with increased risk of thrombosis and transformative progression in some cases. Allele burden (the proportion of cells carrying the mutation) can influence disease phenotype and, in some contexts, prognosis and response to therapy.

Diagnosis and testing: JAK2 V617F testing is a standard component of evaluating suspected myeloproliferative neoplasms. Testing uses allele-specific PCR, quantitative PCR, or sequencing on peripheral blood or bone marrow samples. The mutation is somatic; monitoring allele burden can help assess treatment response or disease evolution.

Therapeutic implications: JAK inhibitors (for example, ruxolitinib) target the pathway and are used in certain cases, particularly myelofibrosis or hydroxyurea-refractory disease. Treatment decisions rely on the overall clinical picture, including age, symptoms, blood counts, and risk of thrombosis.