JAK2 mutations in myeloproliferative neoplasms: a 2008 update

In the spring of 2005, four teams have nearly simultaneously published the description of a point mutation in the tyrosine-kinase JAK2 found in the majority of patients suffering from MyeloProliferative Neoplasms (MPN): transversion G1849T resulting in the substitution V617F. Functional studies as well as animal models confirmed the importance of this mutation in the genesis of MPDs. This discovery promptly affected the management of MPD patients, particularly for diagnostic work up of polyglobulies and thrombocytoses. The JAK2V617F mutation is frequently found (95%) in patients with Polycythemia Vera (PV), less often in patients suffering from essential thrombocythemia (ET) (50-70%) or Primary myelofibrosis (PM) (around 50%). The mutational load (fraction of mutated alleles) also Tires ... part : varies depending on the disease, typically high in PV and PM, weaker in ET. These differences rely on both the proportion of mutated cells and the status (homo vs. heterozygous) of these cells. The presence of the JAK2V617F mutation, and possibly the mutational load, impact the clinico-biological presentation and evolutive profile of MPDs. The various techniques designed for the quantification of mutant burden also allow for a follow up of the efficiency of treatments, either pharmacological (interferon, upcoming JAK2 inhibitors), or immunological (BMT, especially in PM patients). Last, the existence of the JAK2V617F mutation in all three Ph-negative MPDs, along with the heterogeneity in the mutational load in these diseases questions the pathophysiology of the mutation. Early on after the initial description of the mutation, two hypotheses were proposed: one suggests that JAK2V617F is responsible for the development of the MPD, the phenotypic variations owing to different genetic backgrounds or to variable JAK2V617F/ JAK2wild-type ratios in the cells. In the second hypothesis, a primary event precedes the outcome of JAK2V617F. Arguments have been gathered in favour of both hypotheses, which are not mutually exclusive.