Genetic Basis of Polycythemia Vera

真性红细胞增多症的遗传基础

• 批准号: 7502148
• 负责人: JOSEF T PRCHAL
• 金额: $ 34.88万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-28 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7502148
• 关键词: Acute leukemia; Affect; Alleles; Architecture; Biochemical; Cell Line; Cells; Chromosomes; Chronic; Chronic Myeloid Leukemia; Clinic; Clinical; Clinical Research; Cloning; Collaborations; Complex; Data; Defect; Development; Dysmyelopoietic Syndromes; Erythroid; Erythropoietin; Event; Family; Family Study; Functional disorder; Funding; Gene Expression; Genes; Genetic; Genome; Genomics; Genotype; Germ Lines; Goals; Growth; Hematologic Neoplasms; Hematopoietic; Hemorrhagic Thrombocythemia; Imatinib mesylate; Individual; JAK2 gene; Knowledge; Messenger RNA; Molecular; Molecular Biology; Mus; Mutate; Mutation; Myeloproliferative disease; Neutrophilic Leukemia; Other Genetics; Pathway interactions; Patients; Pharmaceutical Preparations; Phenotype; Philadelphia Chromosome Negative Chronic Myelogenous Leukemia; Polycythemia Vera; Predisposition; Primary Myelofibrosis; Proteins; Public Health; Purpose; Range; Research Personnel; Tyrosine Kinase Inhibitor; base; bcr-abl Fusion Proteins; cellular targeting; gain of function mutation; leukemia; member; mutant; progenitor; programs; research study; response; segregation; tyrosine kinase ABL1

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.

真性红细胞增多症 (PV) 是最常见的骨髓增殖性疾病。本项目与本项目的相关性 公共健康的关键在于，对PV分子缺陷的阐明将导致PV的特异性治疗和最终治愈。 根据我们之前的研究，我们假设PV是由几个基因表达的变化引起的 水平。复制并提供了我们对 9p 号染色体单亲二体性发现的鉴定 这是最近在 9p 染色体上发现组成型活性突变体 JAK2 V617F 的基础，即 存在于大多数真性红斑狼疮患者中：JAK2 在单个等位基因中发生突变，并转化为纯合性 约 30% 的真性红斑狼疮患者通过单肠二体性出现。然而，JAK2 V617F 的改动并不能完全解释 PV 的病理生理学。 1) 我们假设完整 PV 表型的发展需要其他遗传事件。在 在这些研究中，我们将进行 a) 通过家庭共同隔离来确定职位候选人 具有PV表型的基因组区域。 b) 通过共享区域识别职位候选人 基因组结构或表达变化，c）我们将利用以下基金来指导我们的基因组分析： 了解 JAK2、其通路和相互作用蛋白，并分析没有 JAK2 的 PV 患者 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；类似的研究将在带有 JAK2 V617F 的多细胞增多小鼠中进行 造血细胞，b) 我们将把 PV 临床反应关联起来（一项正在进行的伊马替尼临床研究） 与 Verstorvsek 博士一起进行甲磺酸盐 - 参见项目 6) 进行甲磺酸伊马替尼及其 JAK2 V617F 基因型和 c) 我们将尝试确定对伊马替尼有反应的患者中 PV 的病理生理学 甲磺酸盐。