Foundations · Year 1 · from Foundations
Case 3: Polycythemia Vera (JAK2 V617F Mutation)
Clinical Image
Source: Wikipedia - Polycythemia vera - CC BY-SA 3.0
Case Presentation
A 65-year-old man presents with facial plethora, pruritus after bathing (aquagenic pruritus), and erythromelalgia (burning pain in his hands and feet). Complete blood count reveals hemoglobin 19.5 g/dL (elevated), hematocrit 58%, WBC 14,000/mm3, and platelets 550,000/mm3. Erythropoietin level is low. Bone marrow biopsy shows hypercellularity with trilineage proliferation. Genetic testing reveals the JAK2 V617F mutation, present in >95% of polycythemia vera cases. The hematologist explains the mechanism: cytokine receptors (including the erythropoietin receptor) lack intrinsic kinase activity and instead associate with JAK kinases. Normally, cytokine binding induces receptor dimerization, bringing JAKs together for trans-phosphorylation and activation, which then phosphorylates STATs that translocate to the nucleus to activate target genes. The V617F mutation in JAK2's pseudokinase regulatory domain causes constitutive kinase activity, leading to erythropoietin-independent proliferation of erythroid precursors. He is treated with phlebotomy to reduce hematocrit below 45%, low-dose aspirin, and eventually ruxolitinib (a JAK1/2 inhibitor) for symptom control and cytoreduction. JAK inhibitors block the constitutively active kinase, providing targeted therapy for myeloproliferative neoplasms.
Key Learning Points
- The JAK-STAT pathway transmits signals from cytokine receptors that lack intrinsic kinase activity; JAKs phosphorylate STATs, which dimerize and translocate to the nucleus to regulate gene expression
- The JAK2 V617F mutation causes constitutive JAK2 activation, leading to cytokine-independent signaling and myeloproliferation; it is found in >95% of polycythemia vera and approximately 50% of essential thrombocythemia and myelofibrosis
- JAK inhibitors (ruxolitinib, fedratinib) provide targeted therapy for myeloproliferative neoplasms by blocking the constitutively active JAK2, demonstrating translation of signaling biology into clinical practice