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）是最常见的骨髓增生性疾病。这个项目的相关性