Polycythemia vera (PV) is a myeloproliferative neoplasm. JAK2 V617F mutation is found in >95% of cases. What is the direct consequence of this mutation at the molecular level?

• A Increased erythropoietin production by the kidney
• B Fusion protein with tyrosine kinase activity spanning JAK2 and calreticulin
• C Constitutive activation of JAK-STAT signaling independent of cytokine binding ✓
• D Loss of CALR inhibition of JAK2 causing unregulated erythropoiesis

Explanation

JAK2 V617F substitution (valine to phenylalanine at position 617) in the pseudokinase regulatory domain removes autoinhibition, resulting in constitutively active JAK2 kinase that phosphorylates STAT3 and STAT5 regardless of cytokine (EPO, TPO, G-CSF) binding. This drives proliferation of all three myeloid lineages. EPO is actually low/normal in PV because the progenitors are hypersensitive to existing EPO. CALR mutations occur in ET and MF without JAK2 mutation.

Reference: Robbins & Cotran Pathologic Basis of Disease, 10th ed.

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

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