Polycythemia Vera (PV) is a myeloproliferative disorder (MPD), whose diagnosis is currently based on an association of clinical and biological criteria following the WHO or the PVSG classification. It is characterized by a primitive absolute erythrocytosis, and formation of endogenous erythroid colonies (EEC). Recently, we described a point mutation in JAK2 (JAK2 V617F) and showed that this activating mutation was the cause of the disease (James et al, Nature, 2005). This molecular abnormality was therefore likely to be a diagnostic marker of PV, as bcr-abl for chronic myeloid leukemia (CML). Nevertheless, JAK2 V617F is also found in other MPDs, sharing some common features with PV, as essential thrombocythemia, idiopathic myelofibrosis, and other rare MPDs. One major criterion for the diagnosis of PV requires the demonstration of increased red cell mass as measured by isotopic methods. We assessed the value of detection of JAK2 V617F as a first intention diagnostic test in 88 patients with hematocrit values above 51% (=erythrocytosis) and showed that the mutation correlated with the diagnosis of PV according to the WHO (R=0.879) and the PVSG (R=0.717) criteria, with a positive predictive value of 100% in the context of erythrocytosis. Besides, the presence of the mutation strongly correlated with EEC formation in 81/87 patients (R=0.824) and only weakly with the serum erythropoietin level (R=0,416). PCR-based genotyping techniques are less time-consuming, less expensive, than DNA sequencing and are easier to perform in hematology diagnostic laboratories. Therefore, we studied the feasibility of the detection of JAK2 V617F with widespread instruments commonly used in routine. We analyzed 119 samples from patients with a suspicion of myeloproliferative disease and showed that JAK2 V617F was efficiently detected by LightCycler® and TaqMan® genotyping technologies, these latter being a little more sensitive than sequencing. For 50 patients, peripheral blood and bone marrow samples were both available. In all cases (34 mutated, 16 non-mutated) the mutation was identically detected. Based on these results, we propose that the detection of JAK2 V617F in granulocytes has a first place in the diagnostic chart of an erythrocytosis, as bcr-abl in CML, avoiding, if positive, an isotopic red cell mass measurement and bone marrow EEC assays. The presence of JAK2 V617F in a patient with erythrocytosis would then lead to the diagnosis of MPD of PV type. Further prospective studies will be necessary to assess if all the MPDs patients bearing JAK2 V617F can be grouped in a new subset within the MPD entity, especially in term of thrombotic and neoplasic risk.

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