JAK2 (V617F) mutation in healthy individuals (2007)

A somatic gain-of-function mutation of the Janus kinase 2 gene (JAK2) is present in most patients with polycythaemia vera, and in about half of those with essential thrombocythaemia and chronic idiopathic myelofibrosis (Passamonti et al, 2006). JAK2 (V617F) mutation confers cytokine-independent growth and cytokine hypersensitivity of cell lines (Baxter et al, 2005). In the last 2 years, more than 700 samples from healthy controls have been studied for JAK2 (V617F) using the following methods: sequencing (Baxter et al, 2005), pyrosequencing (Jones et al, 2005), allele-specific polymerase chain reaction (AS-PCR) (Baxter et al, 2005; Passamonti et al, 2006) and amplification refractory mutation system (ARMS) (Jones et al, 2005): no JAK2 (V617F)-positive cases were found. Recently, two groups found this mutation in healthy populations. Sidon et al (2006) found the mutation in five of 52 individuals, while Xu et al (2006) found the mutation in 37 of 3935 blood samples from donors. Analysing clinical data from Xu's study (Xu et al, 2006), all JAK2 (V617F)-positive individuals but one had blood count abnormalities that may indicate an underlying chronic myeloproliferative disorder. Here, we report a study of JAK2 (V617F) mutation in 75 normal subjects referred to the Outpatient Section of the Department of Haematology of Pavia. These healthy individuals (aged from 18 to 79 years) displayed a normal blood cell count without spleen enlargement. Applying AS-PCR as previously described (Passamonti et al, 2006), we did not find the mutation in any case. In addition, 89 individuals with reactive conditions were evaluated. Forty-four subjects with high erythropoietin level and hypoxia (chronic obstructive pulmonary disease), or tumours had erythrocytosis (haematocrit > 50%), 34 individuals with iron deficiency or inflammatory diseases had thrombocytosis (platelet count > 400 × 109/l), and 11 had a leucocyte count > 12 × 109/l (smokers or with infectious disease). The mutation was not detected in any of them. The different sensitivities of the methods applied in these studies should be taken into account for the interpretation of results. Sequencing has a sensitivity of 20% (Baxter et al, 2005), meaning that at least 20% of alleles must carry the mutation to be detected, while ARMS or AS-PCR has a sensitivity of 1–2% (Jones et al, 2005). In the two recent papers, more sensitive assays were applied: nested AS-PCR (sensitivity 0.25%) (Xu et al, 2006) and a method combining both molecular beacon and locked nucleic acid technologies (sensitivity 0·01%) (Sidon et al, 2006). However, by applying a method with a sensitivity similar to this latter study, McClure et al (2006) did not find a JAK2 (V617F)-positive case within 48 healthy subjects. Another hypothesis to explain JAK2 (V617F) in healthy subjects is that the first progenitor to harbour JAK2 (V617F) might be more differentiated in healthy subjects than in patients with a chronic myeloproliferative disorder. At this stage, the self-renewal potential and the capacity to differentiate of the mutated cell are decreased and the clone it generates might be prone to die. In this hypothesis, the mutated clone does not generate a clinical phenotype and it may disappear at serial evaluation. Conversely, in polycythaemia vera and in myelofibrosis, the JAK2 (V617F) mutation is harboured in a lympho-myeloid progenitor cell (Delhommeau et al, 2006). Sidon et al (2006) hypothesised that discovering the mutation in healthy subjects raised the possibility that the mutation is harboured before the occurrence of the chronic myeloproliferative disorder. This should be confirmed by an adequate follow-up of healthy subjects who carry the mutation. However, the annual incidence of polycythaemia vera and essential thrombocythaemia is very low, ranging from 2·0 to 2·5 per 100 000 person-years. Thus, if JAK2 (V617F) mutation occurs in healthy individuals at a frequency ranging from 1 to 10%, this frequency would be much higher than expected in the early detection of clinical chronic myeloproliferative disorders. This study was supported by grants from Fondazione Cariplo, Milan, Associazione Italiana per la Ricerca sul Cancro (AIRC), Milan, Fondazione Ferrata Storti, Pavia, and Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Policlinico San Matteo, Pavia, Italy.