The JAK2 V617F allele burden in essential thrombocythemia, polycythemia vera and primary myelofibrosis - impact on disease phenotype

Background and objectives: The JAK2 V617F tyrosine kinase mutation is present in the great majority of patients with polycythemia vera (PV), and approximately half of the patients with essential thrombocythemia (ET) and primary myelofibrosis (PMF). The three distinct disease entities may be considered as three phenotypic presentations of the same JAK2 V617F positive chronic myleoproliferative disorder. Together with physiological and genetic modifiers the phenotype may be determined by the JAK2 V617F allele burden. In the present study, we aimed to asses the JAK2 mutational load and its impact on phenotype. Methods: A highly sensitive real-time quantitative PCR (qPCR) assay was used for quantification of the JAK2 V617F mutational load in 165 patients with Philadelphia chromosome negative chronic myeloproliferative disorders (ET = 40, PV = 95, PMF = 30). Results: We provide evidence of increasing JAK2 V617F allele burden from ET, over PV to PMF (P = 0.001 and P < 0.00001 respectively). The present data suggests the JAK2 V617F allele burden as a key determinant of the degree of myeloproliferation and myeloid metaplasia reflected by significantly higher levels of white blood cell counts (WBC) (P = 0.03), CD34 counts (P = 0.03), lactate dehydrogenase and Polycythemia Rubra Vera gene 1 levels (P = 0.03 and P < 0.00001 respectively), as well as lower platelet counts (P = 0.02) and more cases of splenomegaly (P = 0.001) in homozygous PV patients compared to their heterozygous counterparts. Conclusion: The present study support the concept of the JAK2 V617F positive chronic myeloproliferative disorders as a biological continuum with phenotypic presentation in part influenced by JAK2 V617F mutational load.