JAK2V617F mutation and allele burden: correlation with morphologic and clinical features and response to therapy in patients with essential thrombocytemia.

The activating Janus kinase 2 mutation (JAK2V617F) has been detected in most patients with Polycythemia Vera (PV), Essential Thrombocythemia (ET) and Primary Myelofibrosis (PMF). Notably, JAK2V617F mutation has been observed in about 50-60% of patients with ET, suggesting a biological heterogeneity of the disease. Evidence suggests that the JAK2V617F mutation is associated with higher erythropoiesis, unchanged or decreased platelet counts, increased risk of thrombosis and bone marrow fibrosis. Histopathological classification of myeloproliferative neoplasms (MPN) cases was correlated with the allelic burden of JAK2V617F using direct sequencing and/or semiquantitative real time PCR allelic discrimination assay. In particular, we assessed the frequency of JAK2V617F mutation in 261 ET patients and the mutation was detected in 162 cases (62%). Clinical and laboratory findings and histomorphological features of ET patients were compared to mutational status. Patients with JAK2V617F mutation presented with significantly higher haemoglobin level and lower platelet count than wild-type patients. Where available, bone marrow (BM) biopsy from ET patients was analysed. The biopsy of cases with JAK2V617F mutation showed a higher marrow cellularity with marked erithroid hyperplasia and a smaller number of total and large megakaryocytes than wild-type cases. Interestingly, the JAK2V617F mutated cases showed a higher number of micromegakaryocytes and dysplastic megakaryocytes and a lower number of stag-horn and clustered megakaryocytes than wild-type cases. No difference in marrow fibrosis was seen. Finally, a correlation with thrombotic events will be studied during the follow-up of about 40 patients. Our results confirm that ET patients with JAK2V617F mutation have a PV-like phenotype (high haemoglobin level and hypercellular marrow). In addition, they show that the JAK2V617F status is strongly associated with a number of changes of the megakaryocyte lineage (hyperplasia, dysplasia, size, nuclear morphology and clustering of megakaryocytes), as detected by the BM biopsy. Therefore, both JAK2V617F mutational status and BM histology could characterize subsets of ET patients with different phenotype, although the significance of the quantitation of JAK2V617F allele burden during follow-up still remains to be determined.