Genetic Basis of Polycythemia Vera

真性红细胞增多症(PV)是最常见的骨髓增生性疾病。本项目与 公共卫生是，对光伏分子缺陷的阐明将导致光伏的特异性治疗和最终治愈。 根据我们以前的研究，我们假设PV是由几个基因表达的变化引起的 级别。我们发现的染色体9p单一肠外二体的鉴定被复制并提供 最近在染色体9p上发现的结构性活性突变体JAK2 V617F的基础是 在大多数PV患者中存在：JAK2在单个等位基因中突变，并转化为纯合子 在大约30%的PV患者中，通过单肠外二体。然而，JAK2V617F的改变并不能完全解释 PV的病理生理学。 1)我们假设完整的PV表型的发育还需要其他的遗传事件。在……里面 这些研究我们将进行a)通过家族共同隔离确定职位候选人 具有PV表型的基因组区域。B)通过以下共同区域确定职位候选人 基因组结构或表达变化，c)我们将使用 JAK2及其通路和相互作用蛋白的知识及对无JAK2的PV患者的分析 V617F突变。 2)a)我们将研究JAK2 V617F在细胞系中的细胞和生化作用，并将其与 酪氨酸激酶抑制剂的作用；类似的研究将在使用JAK2 V617F的红细胞增多症小鼠中进行。 造血细胞，b)我们将关联PV的临床反应(正在进行的伊马替尼临床研究 与Verstorvsek博士一起甲磺化-见项目6)与他们的JAK2 V617F基因型和 表达，c)我们将尝试确定对伊马替尼有反应的患者的PV的病理生理学 甲磺酸。

Polycythemia vera (PV) is the most common myeloproliferative disorder. Relevance of this project to the public health is that elucidation of molecular PV defect will result in specific therapy and eventual cure of PV. Based on our previous studies, we hypothesize that PV is caused by changes in gene expression at several levels. Identification of our finding of the chromosome 9p uniparenteral disomy was reproduced and provided the basis for the recent discovery of the constitutively active mutant JAK2 V617F on chromosome 9p that is present in the majority of PV patients: JAK2 is mutated in a single allele and it is converted to homozygosity by uniparenteral disomy in approximately 30% of PV patients. However, the JAK2 V617F alteration does not fully explain the pathophysiology of PV. 1) We hypothesize that other genetic events are needed for the development of the full PV phenotype. In these studies we will pursue a) identification of positional candidates through familial co-segregation of genomic regions with the PV phenotype. b) identification of positional candidates by shared regions of genome architecture or expression changes, c) we will guide our genomic analyses by using the fund of knowledge about JAK2, its pathways and interacting proteins, and analyzing those PV patients without JAK2 V617F mutation. 2) a) We will study the cellular and biochemical effect of JAK2 V617F in cell lines and correlate these with the effect of tyrosine kinase inhibitors; similar studies will be done in polycythemic mice with JAK2 V617F in hematopoietic cells, b) We will correlate the PV clinical response (an ongoing clinical study of imatinib mesylate with Dr. Verstorvsek - see project 6) to imatinib mesylate with their JAK2 V617F genotype and expression, c) We will attempt to identify the pathophysiology of PV in those patients who respond to imatinib mesylate.