What Causes Polycythemia Vera
Polycythemia vera is a clonal hematopoietic stem cell disorder of unknown etiology, with the JAK2V617F mutation present in over 95% of cases serving as the key pathogenic driver, though the ultimate cause of this mutation remains unidentified. 1
Primary Pathogenic Mechanism
PV arises from an acquired somatic mutation in a multipotent hematopoietic stem cell, making it a clonal neoplasm that results in overproduction of phenotypically normal blood cells 2, 3
The JAK2V617F mutation (a point mutation in exon 14 of the JAK2 tyrosine kinase gene) is present in >95% of patients and is capable of inducing constitutive STAT5-mediated signaling and erythrocytosis 2, 1
This mutation causes erythropoietin-independent erythroid colony formation and hypersensitivity to multiple hematopoietic growth factors, which explains the autonomous red blood cell production characteristic of PV 2
Unknown Ultimate Etiology
Despite identification of the JAK2V617F mutation, the specific trigger or event that causes this genetic mutation to occur in the first place remains unknown 4, 2
PV was first described in 1892, and over a century later, the fundamental cause of why patients develop the JAK2 mutation is still not understood 2
Additional Genetic Complexity
Over 50% of PV patients harbor DNA sequence variants beyond JAK2, most frequently TET2 (18%) and ASXL1 (15%), suggesting additional genetic events contribute to disease phenotype 5
Approximately 15-20% of patients have abnormal karyotypes, with the most frequent being +9 (5%), loss of chromosome Y (4%), +8 (3%), and 20q- (3%) 5
Some patients (approximately 5%) with classical PV lack the JAK2V617F mutation entirely, indicating alternative pathogenic mechanisms exist 2
Classification as Clonal Stem Cell Disorder
- PV is classified as a chronic myeloproliferative disorder (now myeloproliferative neoplasm), grouped with essential thrombocythemia and primary myelofibrosis based on shared clonal stem cell origin involving both myeloid and lymphoid lineages 4
Epidemiologic Considerations
- PV has a minimum incidence of 2.6 per 100,000 and is particularly prevalent in persons of Ashkenazi Jewish ancestry, suggesting possible genetic predisposition in certain populations 2
Important Clinical Caveat
The JAK2V617F mutation alone cannot establish a diagnosis of PV, as this mutation is also found in essential thrombocythemia and primary myelofibrosis patients, making it a necessary but not sufficient cause of the specific PV phenotype 2. The mutation explains the mechanism of disease but not why it occurs in the first place.