We have recently reported that the somatic V617F JAK2 mutation could be heterogeneously distributed within families with MPD (Bellanne-Chantelot et al, Blood, 108, 346). These families are characterized by at least 1 affected patient with the mutation (JAK2-positive) and 1 or 2 affected relatives without the mutation (JAK2-negative). We have analyzed 18 such families: 3 with polycythemia vera (PV), 7 with essential thrombocythemia (ET), 1 with myelofibrosis and myeloid metapasia (MMM) and 7 families with 2 types of MPD (PV and ET). The median age at diagnosis was not significantly different between the 2 groups considering PV and ET independently. The analysis of 25 patients with ET (11 JAK2-positive and 14 JAK2-negative patients) revealed no difference in the platelet count (950x109/L versus 1004x109/L, respectively). Hemoglobin level and hematocrit were higher in the group of JAK2-positive patients: (144 g/L versus 130 g/L, p=0.009) and (43% vs 39%, p=0.02). Likewise in the same group, endogenous erythroid colonies were more significantly frequent compared to JAK2-negative patient group. As for PV, the sole difference observed between the 2 groups of patients (10 JAK2-positive and 4 JAK2-negative patients) was the higher level of white blood cells (13x109/L vs 6.5x109/L, p=0.01) in the group of PV JAK2-positive patients. All the 39 patients but 2 were treated. Among the JAK2-positive patients, one PV patient developed an acute myeloblastic leukemia and another one a secondary MMM. In the JAK2-negative group, a ET patient developed an acute megakaryoblastic leukemia. Death occured in 7/22 JAK2-positive patients and in 4/20 negative patients. We were able to confirm after a delay of 4 to 7 years the V617F JAK2 genotype in a subset of affected patients. The proportion of the mutant JAK2 allele has increased in a range of 5 to 50% in patients initially diagnosed with the V617F JAK2 mutation. By contrast, the mutation remains absent in patients initially JAK2-negative. We therefore hypothesize that other somatic mutations may be implicated in the development of MPD in JAK2-negative patients in these families. It has been recently suggested that alterations in cytokine receptors, the erythropoietin receptor (EPOR) and thrombopoietin receptor (MPL), might lead to activation of the JAK-STAT signaling pathway in patients negative for the V617F mutation. We have screened by sequencing two regions known to be involved in receptor dimerization (transmembrane domain) and JAK2 binding (juxtamembrane domain). No mutations were identified in these critical regions of EPOR and MPL. In conclusion, this study highlights the variable clinical expression of MPD within these families heterogeneous for the V617F JAK2 mutation. The hematological phenotype seems restricted to a specific lineage in the group of JAK2-negative patients. However, the course of the disease was similar in both groups. The absence of mutations in EPOR and MPL cytokine receptors raised the issue of other genes that are not JAK2-mediated and that might be involved in the occurrence of MPD within these families.

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