Sex differences in the JAK2V617F allele burden in chronic myeloproliferative disorders

Abstract

BackgroundThe JAK2 V617F allele burden is a variable measure, determined by the frequency of mitotic recombination events and the expansion of JAK2 V617F clones. Since variability in the JAK2 V617F allele burden is partly responsible for the distinct phenotypes seen in the myeloproliferative disorders, the objective of this study was to identify modifiers of the allele burden. Design and MethodsBlood samples were obtained between May 2005 and January 2009 from 272 patients with essential thrombocytosis, polycythemia vera, and myelofibrosis. The JAK2 V617F allele burden was measured by an allele-specific quantitative polymerase chain reaction using DNA from purified neutrophils. Repeated measures, on average 2 years apart, were available for 104 patients. ResultsSex, age at diagnosis, and disease duration all independently influenced the JAK2 V617F allele burden. When considering all patients with myeloproliferative disorders, women had significantly lower allele burdens than men (P=0.04). In those patients with repeated measures, the increase in allele burden per year between the first and second evaluations was significantly less in females than in males. Among those who experienced disease evolution, females were 4.5 times more likely to have evolution from essential thrombocytosis to polycythemia vera, but 0.23 times as likely to have evolution from essential thrombocytosis to myelofibrosis. ConclusionsSex is an independent factor accounting for variability in the JAK2 V617F allele burden. We speculate that lower allele burdens in females reflect a lower frequency of mitotic recombination events in females than in males, and should be considered when evaluating the relationship of allele burden to disease phenotype and also in evaluating responses to JAK2 V617F -inhibitors. Because sex may influence genotype and/or clonal expansion, underpinning the variability in JAK2 V617F allele burden, it will be important to explore factors that determine susceptibility to mitotic recombination events. disorders. Haematologica 2010;95:1090-1097. doi:10.3324/haematol.2009 This is an open-access paper. Sex differences in the JAK2

MicroRNA deregulation in polycythemia vera and essential thrombocythemia patients

“…Consistent with the phenotypic and genotypic differences between male and female PV patients [31][32][33][34], there are different miRNA deregulations between male and female patients (Fig. 1).…”

“…Since erythrocytosis is the only feature that distinguishes PV from ET, we also compared specific miRNA expression in the nucleated erythroid cells directly descended from the burstforming unit erythroid (BFU-E) progenitor cells of PV and ET patients. Our data indicate that significant miRNA deregulation occurs in the CD34+ cells of PV patients and confirm a genetic basis for the gender-specific differences that characterize PV [31][32][33][34]. The results of our study also suggest that deregulated miRNAs may represent an important mechanism by which the PV erythrocytosis and ET thrombocytosis phenotypes are determined.…”

“…The stem cell compartment in MPN is heterogeneous with the presence of both JAK2 wild-type clones and JAK2 V617F mutant clones in most MPN patients. In PV, there is usually a gradual increase in the JAK2 V617F mutant stem/progenitor cell population over time with a decrease in the normal stem cell population [32,43]. The effects of miR-196b down-regulation in JAK2 V617F -positive clonal expansion and increased erythroid proliferation in PV are worth further exploration (Fig.…”

“…Given the phenotypic and genotypic differences between male and female PV patients [31][32][33][34], we analyzed differential miRNA expression separately by gender to identify genderspecific effects. Consistent with their different phenotypes, 79 miRNAs were differently regulated in the male PV patients (42 up and 37 down-regulated, p<0.05) compared to healthy male controls, while only 25 miRNAs were differently regulated in the female PV patients (9 up and 16 down-regulated, p<0.05) compared to healthy female controls.…”

Identification of JAK2V617F Mutation on Myeloproliferative Disorders in Medan

“…Late-stage idiopathic myelofibrosis was characterised by bone marrow fibrosis, cytopenia, and splenomegaly and can also transform to acute myeloid leukaemia [4]. PV disease was most prevalent in old age, it can be explained that the increase of the allele was increased with age and the appearance of clinical symptoms and complications were not directly show after the onset of mutations, but mutations takes approximately 12 years to cause symptoms and complication [24].…”