Molecular Pathogenesis of Polycythemia Vera

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DESCRIPTION (provided by applicant): The long-term objective of this research project is to define the molecular basis of polycythemia vera (PV). We previously identified unique molecular defects in thrombopoietin (TPO) receptor (Mpl) gene expression that were associated clinically with distinct myeloproliferative phenotypes. We have now identified a JAK2 gene mutation which was also intimately associated with myeloproliferative disease clinical phenotypes in a gene dosage-dependent manner. We have also observed that gene expression profiling of PV peripheral blood (pb) CD34+ cells not only permitted the diagnosis of PV but also identified heterogeneity amongst PV patients with respect to disease behavior. Importantly, PV patients with aggressive versus indolent disease as defined by gene expression profiling exhibited different combinations of JAK2 and Mpl genetic and epigenetic defects. Thus we hypothesize that PV is a polygenic disorder and that cumulative abnormalities of the JAK2 gene and Mpl are required to generate a PV. We hypothesize that these cumulative defects are responsible for the variability of myeloproliferative disease phenotypes. We also hypothesize that mutant JAK2 gene expression and function is integrally involved on the pathogenesis of PV through aberrant signal transduction and Mpl protein processing abnormalities. To test these hypotheses, we propose to define the effect of mutated JAK2 on intracellular signal transduction and Mpl expression and function, to define the relationship between mutated JAK2 and Mpl genetic and epigenetic alterations in PV patients with respect to disease phenotype and to determine whether PV clinical phenotypes as defined by PV blood and marrow CD34+ cell gene expression profiling and JAK2/Mpl genetic defects are recapitulated by xenotransplantation of these cells in NOD/SCID mice. (End of Abstract)