Molecular Pathogenesis of Polycythemia Vera

描述(由申请人提供)： 本研究项目的长期目标是明确真性红细胞增多症(PV)的分子基础。我们先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临床上不同的骨髓增殖性表型有关。我们现在已经发现了JAK2基因突变，该突变也与骨髓增生性疾病的临床表型密切相关，且呈基因剂量依赖性。我们还观察到，PV外周血(PB)CD34+细胞的基因表达谱不仅可以用于PV的诊断，还可以确定PV患者在疾病行为方面的异质性。重要的是，根据基因表达谱定义，侵袭性和惰性疾病的PV患者表现出不同的JAK2和MPL遗传和表观遗传缺陷组合。因此，我们假设PV是一种多基因疾病，JAK2基因和MPL的累积异常是发生PV所必需的。我们假设这些累积缺陷是骨髓增殖性疾病表型变异的原因。我们还假设突变的JAK2基因的表达和功能通过异常的信号转导和MPL蛋白加工异常完整地参与了PV的发病。为了验证这些假说，我们建议确定突变的JAK2对细胞内信号转导和MPL表达和功能的影响，确定突变的JAK2和MPL基因和表观遗传学改变与疾病表型的关系，并确定这些细胞异种移植到NOD/SCID小鼠后，是否再现了PV血液和骨髓CD34+细胞基因表达谱所定义的PV临床表型和JAK2/MPL基因缺陷。(摘要结束)

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)