Molecular Pathogenesis of Polycythemia Vera

描述（由申请人提供）： 本研究项目的长期目标是确定真性红细胞增多症（PV）的分子基础。 我们以前发现血小板生成素（TPO）受体（Mpl）基因表达的独特分子缺陷与不同的骨髓增生性表型临床相关。我们现在已经确定了JAK 2基因突变，该突变也以基因剂量依赖性方式与骨髓增生性疾病临床表型密切相关。我们还观察到，PV外周血（pb）CD 34+细胞的基因表达谱不仅允许诊断PV，而且还确定了PV患者之间的异质性疾病行为。重要的是，如通过基因表达谱所定义的，具有侵袭性与惰性疾病的PV患者表现出JAK 2和Mpl遗传和表观遗传缺陷的不同组合。因此，我们假设PV是一种多基因疾病，并且需要JAK 2基因和Mpl的累积异常来产生PV。我们假设这些累积的缺陷是骨髓增生性疾病表型变异的原因。我们还推测突变型JAK 2基因的表达和功能通过异常的信号转导和Mpl蛋白加工异常参与PV的发病机制。为了验证这些假设，我们提出确定突变的JAK 2对细胞内信号转导和Mpl表达和功能的影响，确定PV患者中突变的JAK 2与Mpl遗传和表观遗传改变之间在疾病表型方面的关系，并确定PV临床表型是否如PV血液和骨髓CD 34+细胞基因表达谱和JAK 2/Mpl基因表达谱所定义。Mpl遗传缺陷通过在NOD/SCID小鼠中异种移植这些细胞来重现。 (End摘要）

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)