Polycythemia vera (PV) is a clonal disorder of unknown etiology arising in a multipotent hematopoietic progenitor cell that is characterized by overproduction of phenotypically normal red cells, white cells and platelets in the absence of a definable cause. Impaired expression of the thrombopoietin receptor, Mpl. occurs in PV and to a lesser extent, idiopathic myelofibrosis (IM) and essential thrombocytosis (ET), while in African Americans, an Mpl point mutation (K39N) was associated with thrombocytosis. Recently, a JAK2 point mutation (V617F) was identified in the majority of PV patients and also in some IM and ET patients. The extent to which each of these molecular abnormalities contributes to the PV phenotype and their relationship to each other is unknown but we hypothesize that both contribute and are integrally related. Using gene expression profiling and unsupervised hierarchical clustering in PV peripheral blood CD34+ cells, we have also been able to segregate PV patients into two groups: those with an aggressive disease and those with a more indolent one. Whether these gene expression profiles reflect the functional behavior of the CD34+ cells and how they relate to the JAK2 V617F mutation is unknown. To address these questions, we plan to develop complementary murine models to study the in vitro and in vivo behavior of murine hematopoietic progenitor cells expressing PV variant Mpl or JAK2 V617F alone or together using the Mpl knockout mouse to dissect Mpl and JAK2 V617F interactions. To control for overexpression of either Mpl or JAK2 V617F, we also plan to examine their behavior using conditional expression in murine ES cells from the Mpl knockout mouse. To examine the functional significance of the gene expression profiles, we plan to study the engraftment kinetics of PV CD34+ cells, their lineage-specific commitment and the extent of extramedullary hematopoiesis after transplantation into NOD-SCID mice. Using flow cytometry and xenotransplantation, we also plan to define by immunophenotyping, the class of CD34+ cell involved in PV. PV is not a new disease but after 11 decades of investigation, its etiology remains unknown and there is no specific therapy for it. We propose to develop complementary animal models for PV that will lead to an understanding of the pathogenesis of PV, that will identify PV patients most at risk from disease complications, and provide a means for testing potential treatments for the disorder.
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