Diagnostic assays for the JAK2 V617F mutation in chronic myeloproliferative disorders.

In 2005, multiple groups identified a high frequency of the V617F (G→T) mutation in the tyrosine kinase gene JAK2 as the most common molecular abnormality in chronic myeloproliferative disorders. Before 2005, there had been no recurring cytogenetic abnormality described at a high incidence in these disorders. The initial descriptions could well be classified as discovery papers because each group used sequencing of the JAK2 gene in established cases of each myeloproliferative disorder.1-5 These studies demonstrated that the highest frequency of this somatic JAK2 mutation occurred in polycythemia vera (65%-97%), with a lesser frequency (23%-57%) in essential thrombocythemia and idiopathic myelofibrosis ❚Table 1❚.1-5 No other mutation site in JAK2 was identified. This unique valine to phenylalanine substitution at position 617 results in proliferative advantages for hematopoietic precursors4 that are hypersensitive to cytokines.3 It is not surprising that JAK2 mutations have been identified at a low incidence in acute myeloid leukemia and in rare cases of myelodysplastic syndrome. It is well known that chronic myeloproliferative disorders may transform into acute leukemia; therefore, some cases may not have manifested in the chronic phase. Other patients have mixed findings in which the differential diagnosis is difficult, such as in chronic myelomonocytic leukemia, which also has been shown to have a low incidence of JAK2 mutations.6 The goal of this editorial is to discuss the development of diagnostic methods for the JAK2 V617F mutation. It is not intended to be a review of the pathogenesis of JAK2 mutations or the clinical correlations identified to date. Why are there variations in the incidence rate in the patient series? This variation likely is due to the different clinical criteria used for diagnosis, the extent of involvement by the clonal proliferation at the time of specimen collection, and the difference in performance by the assays used to detect the mutation.