Genetic Analysis of Myeloproliferative Disease

骨髓增生性疾病的遗传分析

• 批准号: 8107678
• 负责人: JOHN K COWELL
• 金额: $ 27.78万
• 依托单位: AUGUSTA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-04-01 至 2013-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8107678
• 关键词: Aftercare; Antibodies; Biological; Biological Models; Bone Marrow Cells; Cell Line; Cell Nucleus; Cell model; Cells; Cellular biology; Chimeric Proteins; Chromosomal translocation; Chromosome abnormality; Chromosomes; Classification; Clinical Management; Constitutional; Cytoplasm; DNA Sequence Rearrangement; Data; Development; Dimerization; Disease; Eligibility Determination; Etiology; Event; FGFR1 gene; Fibroblast Growth Factor Receptor 1; Future; Gene Expression; Genes; Genetic; Growth; Heat-Shock Proteins 70; Hematopoietic; Knockout Mice; Leukemic Cell; Ligand Binding; Link; Lymphoid; MADH3 gene; Mass Spectrum Analysis; Membrane; Modeling; Molecular; Molecular Biology; Multipotent Stem Cells; Mus; Mutation; Myelogenous; Myeloid Leukemia; Myeloproliferative disease; Oncogenic; Other Genetics; Pathogenesis; Pathway interactions; Patients; Phenotype; Phosphorylation; Phosphotransferases; Phosphotyrosine; Process; Protein Analysis; Protein Tyrosine Kinase; Proteins; Proteomics; Reagent; Relapse; Research Proposals; Residual Neoplasm; Role; SERPINB2 gene; Series; Stem cells; Symptoms; System; T-Cell Leukemia; T-Cell Lymphoma; T-Lymphocyte; Translating; Transplantation; Treatment Protocols; Variant; Western Blotting; Zinc Fingers; base; cell type; design; fusion gene; genetic analysis; human disease; in vivo Model; insight; leukemia; leukemia/lymphoma; leukemogenesis; mouse model; novel; retroviral transduction; sumo1 gene; tumor; tumor progression; tumorigenesis; vector

DESCRIPTION (provided by applicant): The characterization of constitutional chromosome translocations in specific types of leukemia has consistently led to an understanding of genes important in leukemogenesis. In some cases this information has been translated to the clinical management of the disease, as well as the reliable identification of structural chromosome rearrangements for the classification of tumors, identification of minimal residual disease after treatment and the prediction of relapse before the onset of symptoms. In particular, the timely identification of the presence of specific rearrangements can often determine the aggressiveness of the treatment regimen which should be used. We have recently characterized the ZNF198/FGFR1 fusion tyrosine kinase gene associated with the highly specific 8;13 translocation which is consistently identified in tumors from patients with an atypical myeloproliferative disease which is associated with T-cell lymphoma and may progress to AML. The involvement of both lineages in this disorder suggests that the structural chromosome rearrangement, which is often the only structural chromosome abnormality in the leukemic cells, occurs in an early progenitor cell before the commitment to the myeloid and lymphoid lineages. This fusion event results in the constitutive activation of the FGFR1 kinase domain through dimerization of the ZNF198 zinc finger motif, which results in mislocalization to the cytoplasm. Genetic studies have implicated a number of leukemia related genes associated with the expression of ZNF198/FGFR1 including PML, ABL, HHR6, SOCS3, SSBP2, SUMO1 and PAI2. To gain a better understanding of the pathways involved in ZNF198/FGFR1 induced leukemogenesis we will use a combination of proteomics and cell and molecular biology approaches to characterize the targets of phosphorylation of this chimeric and extend these studies to three variant, FGFR1 activating rearrangements. We have developed an in vivo model of ZNF198/FGFR1 which produces an MPD-like disease following retroviral transfer of the fusion kinase into primary bone marrow cells using an MSCV based vector. Similar models have been created for the other variant rearrangements. These tumors are transplantable to new hosts. Tumors from these mice will be used to investigate the genetic events that contribute to tumor progression. We will use a series of reagents developed for this project to undertake a series of cellular biology analyses designed to characterize the significance of the dysregulated pathways associated with ZNF198/FGFR1 expression. A deeper insight of the molecular consequences of 6

描述（由申请人提供）：特定类型白血病中宪法染色体易位的表征始终导致对在白血病生成中重要的基因的理解。在某些情况下，这些信息已转化为对该疾病的临床管理，以及可靠地鉴定出肿瘤分类的结构染色体重排，治疗后最小残留疾病的鉴定以及症状发作之前的复发预测。特别是，及时确定特定重排的存在通常可以确定应使用的治疗方案的侵略性。我们最近表征了ZnF198/FGFR1融合酪氨酸激酶基因与高度特异性8; 13易位相关的易位，该基因在患有非典型骨髓骨化性脊髓性疾病的患者的肿瘤中始终鉴定出来，该疾病与T-Cell淋巴瘤有关，并可能发展为AML。两种谱系在这种疾病中的参与表明，在对髓样细胞和淋巴样链球菌的承诺之前，这通常是白血病细胞中唯一的结构性染色体异常。这种融合事件通过ZnF198锌指基序的二聚化导致FGFR1激酶结构域的组成型激活，从而导致细胞质错误定位。遗传研究暗示了许多与ZnF198/FGFR1表达相关的白血病相关基因，包括PML，ABL，HHR6，SOCS3，SSBP2，SUMO1，SUMO1和PAI2。为了更好地了解ZNF198/FGFR1诱导的白血病发生的途径，我们将使用蛋白质组学和细胞和分子生物学方法的组合来表征该嵌合的磷酸化靶标，并将这些研究扩展到三个变体FGFR1激活重排。我们已经开发了ZnF198/FGFR1的体内模型，该模型使用基于MSCV的载体将融合激酶逆转录病毒转移到原代骨髓细胞中后产生MPD样疾病。为其他变体重排创建了类似的模型。这些肿瘤可移植到新宿主。这些小鼠的肿瘤将用于研究导致肿瘤进展的遗传事件。我们将使用为该项目开发的一系列试剂来进行一系列旨在表征与ZNF198/FGFR1表达相关的失调途径的意义的细胞生物学分析。对6的分子后果的深入了解