Heterogeneous Distribution of the JAK2 Val617Phe Activating Mutation in Familial Myeloproliferative Disorders.
Authors: Bellanne-Chantelot Christine , Labopin Myriam , Chaumarel Isabelle , Delhommeau Francois , Leroy Gwendoline , Bellanger Florence , Thomas Gilles , Vainchenker William , Najman Albert 
Published: April 2020

Abstract
An activating mutation Val617Phe of the tyrosine kinase JAK2 has recently been reported by several groups in the majority of patients with polycythemia vera (PV) and approximately half of those with either essential thrombocythemia (ET) or myelofibrosis with myeloid metaplasia (MMM). These haematological malignancies characterized by a stem cell-derived clonal proliferation of myeloid cells are traditionally subgrouped as myeloproliferative disorders (MPD). Until now, the JAK2 mutation has been described in sporadic cases of MPD but the prevalence of this mutation in familial MPD is unknown. Genomic DNA from peripheral blood mononuclear cells of 129 familial cases of MPD - 60 with PV, 61 with ET and 8 with MMM - were screened by sequencing for the JAK2 Val617Phe (1849 G&gt;T) mutation. The mutant T allele was detected in 81 of 129 familial MPD: 45 (75%) with PV, 30 (50%) with ET and 6 (75%) with MMM. The T allele was the major allele (&gt;50% of peak height) in 20% and 25% of patients with PV or MMM respectively compared to 8% in patients with ET. Moreover, 3 first degree relatives with endogenous erythroid colonies and with normal blood cell counts were also carriers of the JAK2 mutation. Then, we analysed the distribution of the JAK2 mutation in 46 families with at least 2 affected cases. In 20 (44%) families, all affected subjects were carriers of the JAK2 mutation. This subgroup included MPD families with homogeneous phenotype (60%) as well as MPD with mixed phenotypes (40%). In 7 (15%) other families including principally families with ET, the JAK2 mutation was not detected in any affected patients; all had the same haematological profile compared to positive-JAK2 patients. Interestingly, in the other 19 (41%) families, the distribution of the JAK2 mutation was heterogeneous consisting of at least one affected patient carrying the JAK2 mutation and one or two affected relatives without the JAK2 mutation. In these discordant families, the absence of the JAK2 mutation was not associated with a specific phenotype. A more severe expressivity of the disease or the occurence of complications were not observed in carriers of the JAK2 mutation. These results highlighted the heterogeneous distribution of JAK2 mutation in familial MPD and may suggest that JAK2 is not a major genetic predisposing factor. This hypothesis was confirmed by a genome-wide linkage analysis performed on the 46 families that excluded as a candidate region the short arm of chromosome 9 in which JAK2 gene is located. Finally, several groups have reported in sporadic cases the absence of the JAK2 mutation in T-cells and non-hematopoietic tissues showing that JAK2 mutation is an acquired myeloid lineage-specific mutation. Preliminary results on T-cells CD3+ and B-cells CD19+ sorted by flow cytometric analysis of peripheral blood from 20 unrelated patients with familial MPD were consistent with those previous results. In conclusion, the prevalence of the JAK2 mutation is similar in sporadic and familial cases of MPD. The observation of (i) a heterogeneous distribution of the JAK2 mutation within families and (ii) the absence of the JAK2 mutation in non myeloid cells corroborate the hypothesis that JAK2 mutation is a somatic event.