Elizabeth Mazoyer

Expression level and differential JAK2-V617F–binding of the adaptor protein Lnk regulates JAK2-mediated signals in myeloproliferative neoplasms

Activating mutations in signaling molecules, such as JAK2-V617F, have been associated with myeloproliferative neoplasms (MPNs). Mice lacking the inhibitory adaptor protein Lnk display deregulation of thrombopoietin/thrombopoietin receptor signaling pathways and exhibit similar myeloproliferative characteristics to those found in MPN patients, suggesting a role for Lnk in the molecular pathogenesis of these diseases. Here, we showed that LNK levels are up-regulated and correlate with an increase in the JAK2-V617F mutant allele burden in MPN patients. Using megakaryocytic cells, we demonstrated that Lnk expression is regulated by the TPO-signaling pathway, thus indicating an important negative control loop in these cells. Analysis of platelets derived from MPN patients and megakaryocytic cell lines showed that Lnk can interact with JAK2-WT and V617F through its SH2 domain, but also through an unrevealed JAK2-binding site within its N-terminal region. In addition, the presence of the V617F mutation causes a tighter association with Lnk. Finally, we found that the expression level of the Lnk protein can modulate JAK2-V617F-dependent cell proliferation and that its different domains contribute to the inhibition of multilineage and megakaryocytic progenitor cell growth in vitro. Together, our results indicate that changes in Lnk expression and JAK2-V617F-binding regulate JAK2-mediated signals in MPNs.

Prothrombin G20210A carriers the genetic mutation and a history of venous thrombosis contributes to thrombin generation independently of factor II plasma levels

Summary.  Background: The prothrombin (PT) G20210A gene mutation is a common risk factor for venous thrombosis (VT), which is mainly mediated through an increase in factor II (FII) plasma levels. High FII plasma levels may act through an increase in endogenous thrombin potential (ETP) a key step in hemostasis and thrombosis. While FII may be the main contributor to ETP in PT G20210A carriers, the knowledge of other environmental or genetic factors influencing ETP may help to better identify those at risk of VT. Aims: ETP was determined in 472 non‐carriers of PT G20210A (PT−) and in 325 unrelated carriers of PT G20210A (PT+) with (symptomatic n = 158) or without (asymptomatic, n = 167) a history of VT. All PT+ were heterozygous and free of other thrombophilic defects.Results: ETP was higher in asymptomatic PT+ than in PT− (2038 ± 371 vs. 1616 ± 267 nmol L−1 min; P < 0.0001). ETP was significantly higher in symptomatic PT+ than in controls PT+ (2129 ± 430 vs. 2038 ± 371 nmol L−1 min; P = 0.01). Multivariate analyses evidenced the importance of FII and fibrinogen plasma levels in determining ETP. Discussion: After taking these variables into account, a personal history of VT remained associated with ETP in PT+ carriers. Moreover, PTG20210A still contributes to ETP after consideration of FII levels. Conclusion: In conclusion, the increase in ETP observed in carriers is not entirely explained by higher FII or fibrinogen plasma levels but also by the history of VT.