Genetic Basis of Polycythemia Vera

真性红细胞增多症的遗传基础

• 批准号: 8064158
• 负责人: JOSEF T PRCHAL
• 金额: $ 46.32万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8064158
• 关键词: Accounting; Acquired uniparental disomy; Acute leukemia; Architecture; BFU-E; Biological Assay; Biology; Blood; Cells; Chromosomes, Human, Pair 6; Clonal Evolution; Clonality; Collaborations; DNA Sequence; Data; Defect; Development; Diagnosis; Disease; Erythroid; Erythropoiesis; Erythropoietin; Event; Evolution; Familial Polycythemia; Family; Frequencies; Generations; Genetic; Genetic Predisposition to Disease; Genome; Genomics; Germ Lines; Germ-Line Mutation; Goals; Haplotypes; Hematologic Neoplasms; Hematopoiesis; Hematopoietic stem cells; Hereditary Malignant Neoplasm; Hyperactive behavior; Hypoxia; Individual; Inherited; Interferons; JAK2 gene; Knowledge; Lesion; Link; MicroRNAs; Molecular; Morbidity - disease rate; Mutation; Myelofibrosis; Myeloid Cells; Myelosuppression; Patients; Phenotype; Play; Polycythemia Vera; Predisposition; Primary Lesion; Protein Tyrosine Kinase; Regulator Genes; Reporting; Research; Research Personnel; Risk; Role; Running; Somatic Mutation; Technology; Therapeutic Intervention; Universities; base; bone marrow hyperplasia; cost; data integration; genome sequencing; insight; loss of function; member; mortality; progenitor; segregation; stem

Polycythemia Vera ( PV) is the most common myeloproliterative disorder. PV is believed to arise from a somatic change of a single hematopoietic stem cell, but both the diagnosis and therapy of PV are controversial as its molecular defect or defects have not been characterized. We conclude that JAK2 V617F is not the cause of clonal proliferation of PV but is preceded by other somatic and germ line mutation(s). Thus we hypothesize that besides the JAK2 V617F mutation, additional genetic events are needed for the development of the full PV phenotype; identification of these is the principal goal of this application. These studies will require the combination and integration of data from several genomics approaches. Based on these considerations we plan to pursue three Specific Aims to accomplish our goal: SA 1. Identification of pre-JAK2 somatic mutations causing clonal hematopoiesis by integration of these complementary approaches: SA 1a. Identification of positional candidates through familial co-segregation of genomic regions with the PV phenotype. SA 1 b. Comparison of clonal and polyclonal cells from individual patients with sporadic PV. SA 1c. Identification of shared regions of genome architecture using the Trio family approach for determination of a predisposing inherited haplotype. SA 1d. The candidate genomic regions will be evaluated in detail by whole exonic genome sequencing and entire whole genome sequencing, as this technology is rapidly advancing and its costs are becoming affordable. Our University is acquiring Pacific biosciences platform capable of analyzing 10kb sequence per run by effort spearheaded by this project co-investigator Dr. Jorde. SA 2. Search for nonconventional genetic lesions; i.e. miRNA. In collaboration with Dr. Croce, we will focus on the region of chromosome 6 as a potential germ-line or acquired contributor to the genesis of PV. SA 3. Determine the sequential genomic changes in PV treated by pegylated interferon a in those patients with decreasing JAK2 V617F allelic burden and return of polyclonal hematopoiesis.

真性红细胞增多症（PV）是最常见的骨髓增生性疾病。PV被认为是由单个造血干细胞的体细胞变化引起的，但是PV的诊断和治疗都是困难的。 由于其分子缺陷或缺陷尚未表征，因此存在争议。 我们得出结论，JAK 2 V617 F不是PV克隆增殖的原因，而是在其他体细胞和生殖系突变之前。 因此，我们假设，除了JAK 2 V617 F突变，还需要额外的遗传事件来发展完整的PV表型;鉴定这些是本申请的主要目标。这些研究将需要结合和整合来自几种基因组学方法的数据。 基于这些考虑，我们计划追求三个具体目标来实现我们的目标： SA 1.通过整合这些互补方法鉴定导致克隆造血的前JAK 2体细胞突变： SA 1a.通过基因组区域与PV表型的家族共分离来识别位置候选者。 SA 1 B.散发性PV个体患者的克隆和多克隆细胞的比较。 SA 1c.使用Trio家族方法鉴定基因组结构的共享区域以确定易感遗传单倍型。 SA 1d.候选基因组区域将通过全外显子基因组测序和整个全基因组测序进行详细评估，因为这项技术正在迅速发展，其成本也变得负担得起。我们的大学正在收购太平洋生物科学平台，该平台能够通过该项目的共同研究者Jorde博士带头的努力分析每次运行的10 kb序列。 SA 2.寻找非常规遗传病变;即miRNA。与Croce博士合作，我们将专注于6号染色体区域作为PV发生的潜在生殖系或获得性贡献者。 SA 3.确定这些患者接受聚乙二醇干扰素a治疗后PV的顺序基因组变化 JAK 2 V617 F等位基因负荷降低，多克隆造血恢复。