What Causes Polycythemia Vera
Polycythemia vera is caused by acquired somatic mutations in the JAK2 gene, most commonly the JAK2 V617F mutation (present in >95% of cases), with a minority having JAK2 exon 12 mutations. 1, 2
Primary Molecular Pathogenesis
The disease originates from a clonal hematopoietic stem cell disorder where oncogenic JAK2 mutations constitutively activate the JAK-STAT signal transduction pathway, leading to uncontrolled production of blood cells independent of normal regulatory mechanisms. 3, 2
Specific Genetic Mutations
JAK2 V617F mutation is the causative mutation in the vast majority of PV cases, creating a constitutively active tyrosine kinase that drives erythropoietin-independent red blood cell production. 1, 3
JAK2 exon 12 mutations account for a small subset of cases that lack the V617F mutation but still present with classical PV features. 2
LNK mutations represent another rare mechanism of JAK-STAT pathway activation in PV. 3
Functional Consequences
The JAK2 V617F mutation induces constitutive STAT5-mediated signaling in vitro and produces erythrocytosis in vivo in mouse models, directly demonstrating its pathogenic role. 2
Clonal Nature and Cell Lineage Involvement
PV is a multipotent hematopoietic progenitor cell disorder affecting not just erythroid cells but also myeloid and even lymphoid lineages, explaining the panmyelosis (increased red cells, white cells, and platelets) characteristic of the disease. 4, 2
Additional Molecular Abnormalities
While JAK2 mutations are the primary driver, over 50% of patients harbor additional DNA sequence variants/mutations beyond JAK2, most frequently:
- TET2 mutations (18% of cases) 1
- ASXL1 mutations (15% of cases) 1
- Prognostically adverse mutations including SRSF2, IDH2, RUNX1, and U2AF1 (combined 5%-10% incidence) 1
These additional mutations likely contribute to disease phenotype and progression but are not the primary causative events. 1
Key Pathophysiologic Features
Erythropoietin-independent erythroid colony formation is the hallmark laboratory finding, reflecting the autonomous growth of PV cells without normal EPO stimulation. 2
Hypersensitivity to multiple hematopoietic growth factors beyond EPO, explaining the multilineage involvement. 2
Defective TPO clearance due to reduced c-mpl membrane expression contributes to thrombocytosis despite elevated platelet mass. 4
Important Clinical Context
The etiology remains fundamentally unknown at the deepest level—we understand the proximate genetic cause (JAK2 mutations) but not why these mutations arise in the first place. 4, 2 The disease is more common than chronic myelogenous leukemia with a minimum incidence of 2.6 per 100,000, and shows particular prevalence in persons of Ashkenazi Jewish ancestry. 2
Critical Diagnostic Caveat
The JAK2 V617F mutation cannot by itself establish a diagnosis of PV because some classical PV patients lack this mutation, and the mutation is also found in other myeloproliferative disorders (essential thrombocythemia and idiopathic myelofibrosis). 2 Diagnosis requires integration of mutation status with clinical and bone marrow findings per WHO criteria. 3