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.

多余细胞增多症（PV）是最常见的骨髓化学障碍。据信PV是由单个造血干细胞的躯体变化引起的，但PV的诊断和治疗都是 尚未表征有争议的，因为其分子缺陷或缺陷尚未表征。 我们得出的结论是，JAK2 V617F不是PV克隆增殖的原因，而是其他体细胞和生殖系突变（S）。 因此，我们假设除了JAK2 V617F突变外，还需要其他遗传事件才能开发完整的PV表型。确定这些是本应用程序的主要目标。这些研究将需要从几种基因组学方法中结合和整合数据。 基于这些考虑因素，我们计划追求三个具体目标以实现我们的目标： SA 1。通过整合这些互补方法来鉴定JAK2体细胞突变，从而导致克隆造血症： SA 1A。通过与PV表型的基因组区域的家族共隔离来鉴定位置候选者。 SA 1 b。来自零星PV患者的克隆和多克隆细胞的比较。 SA 1C。使用三重奏家族方法来确定基因组架构共享区域，以确定易感的遗传单倍型。 SA 1D。候选基因组区域将通过整个外显子基因组测序和整个基因组测序进行详细评估，因为该技术正在迅速发展，其成本越来越便宜。我们的大学正在收购Pacific Biosciences平台，该平台能够通过该项目共同投资者Jorde博士率领的努力来分析每次运行的10KB序列。 SA 2。寻找非惯性遗传病变；即mirna。与Croce博士合作，我们将专注于6号染色体区域，作为潜在的种系或获得PV起源的贡献者。 SA 3。确定这些患者在这些患者中通过phyated干扰素A治疗的PV的顺序基因组变化 随着JAK2 V617F等位基因负担的减少和多克隆造血的返回。