Etiology of translocations in hematopoietic cells

造血细胞易位的病因学

基本信息

批准号：
7622901
负责人：
Christine A. Richardson
金额：
$ 26.4万
依托单位：
UNIVERSITY OF NORTH CAROLINA CHARLOTTE
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-05-19 至 2009-10-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7622901
关键词：
11q23 9,10-anthraquinone Alkylating Agents Anthracycline Antibiotics Anthracyclines Anthraquinones Antigen Receptors Benzene Bone Marrow Cells Chromosomal Rearrangement Chromosomal translocation Chromosome Band Chromosome Banding Class Clinical Cocoa Powder Coffee Cultured Cells DNA DNA Damage DNA Repair DNA Sequence Rearrangement DNA biosynthesis Development Double Strand Break Repair ES Cell Line Endonuclease I Epipodophyllotoxin Compound Etiology Etoposide Event Exposure to Frequencies Fruit Funding Generations Genes Genetic Genetic Recombination Genome Genomics Grant Green Fluorescent Proteins Hematopoietic Hematopoietic stem cells Human Infant Knock-in Mouse Lead Lymphoid Cell MLL gene MLLT3 gene Malignant Neoplasms Mammalian Cell Measures Metabolism Molecular Monitor Mus Myelogenous Oncogenic Perinatal Exposure Pesticides Prevention therapy Quinolone Antibiotic Range Recombinants Reporter Research Risk Stem cells System Tea Therapy-Related Acute Myeloid Leukemia Topoisomerase II Topoisomerase-II Inhibitor Translocation Breakpoint Treatment Protocols Wine Yeasts abstracting base cohort embryonic stem cell endodeoxyribonuclease SceI in vivo inhibitor/antagonist insight irradiation laxative leukemia leukemia/lymphoma leukemogenesis mouse model novel strategies peripheral blood podophyllin programs repaired sarcoma soy

项目摘要

Project Abstract: The long-term objective of my research is to understand the influence of hematopoietic-specific developmental programs on the repair DNA damage such as double strand breaks (DSBs) and the initial molecular events that lead to translocations, which are a hallmark of leukemia, lymphoma, and soft-tissue sarcomas. DSBs are highly recombinogenic, increasing the exchange of information between two homologous DNA duplexes by several orders of magnitude; thus, mammalian cells are potentially at risk for rearrangements arising during DSB repair. Chromosomal DSBs result following exposure to irradiation, alkylating agents, and topoisomerase II (topoII) inhibitors that are common therapies in the treatment of human cancers. Treatment regimens that include the topoII inhibitor etoposide are associated with one class of therapy-related acute myeloid leukemia (t-AML) and chromosomal translocations involving the mixed lineage leukemia (MLL) gene on chromosome band 11q23. Similarity of 11q23 MLL breakpoints in t-AML and infant leukemias suggests an association between de novo infant leukemia and in utero exposure to topoII inhibitors. The list of potential topo II inhibitors is extensive, and it remains unclear which of these compounds have a direct potential to induce the chromosomal translocations observed in the clinical setting. Using a unique genetic system to determine the potential for repair of DSBs within the breakpoint cluster regions of the 11q23 MLL gene and common partner genes to result in chromosomal translocations, this proposal will (1) determine the potential for exposure to topoII inhibitors to initiate chromosomal rearrangements within the breakpoint cluster region of the MLL and AF9 genes similar to those observed in the clinical setting; and (2) create a targeted mouse model to determine in vivo the potential for exposure to topoII inhibitors to initiate chromosomal rearrangements within the breakpoint cluster region of the MLL and AF9 genes as measured by the presence of MLL-AF9 genome rearrangements in bone marrow and peripheral blood. These unique approaches in both ex vivo cell culture and in vivo mouse models will provide significant insight into the initiation of potentially oncogenic chromosomal rearrangements and leukemogenesis. Unraveling the etiology and consequences of translocations may lead to new approaches to therapy and prevention.

项目摘要：我研究的长期目标是了解造血特异性的影响修复 DNA 损伤（例如双链断裂 (DSB)）和导致易位的初始分子事件，这是白血病、淋巴瘤和癌症的标志软组织肉瘤。 DSB 具有高度重组性，可增加 DSB 之间的信息交换两个同源 DNA 双链体有几个数量级；因此，哺乳动物细胞有可能存在 DSB 修复期间发生重排的风险。暴露于以下物质后会产生染色体 DSB 放射治疗、烷化剂和拓扑异构酶 II (topoII) 抑制剂是常见的治疗方法人类癌症的治疗。包括拓扑异构酶 II 抑制剂依托泊苷的治疗方案是与一类治疗相关的急性髓系白血病 (t-AML) 和染色体涉及染色体带 11q23 上的混合谱系白血病 (MLL) 基因的易位。 t-AML 和婴儿白血病中 11q23 MLL 断点的相似性表明 de 新婴儿白血病和子宫内暴露于拓扑异构酶II抑制剂。潜在拓扑 II 抑制剂列表是广泛的，目前尚不清楚这些化合物中哪些具有直接诱导的潜力在临床环境中观察到的染色体易位。利用独特的遗传系统确定 11q23 MLL 基因断点簇区域内 DSB 修复的潜力和共同伴侣基因导致染色体易位，该提案将（1）确定暴露于拓扑异构酶 II 抑制剂可能引发染色体重排 MLL 和 AF9 基因的断点簇区域与临床环境中观察到的相似； (2) 创建靶向小鼠模型以确定体内暴露于 topoII 的可能性在 MLL 的断点簇区域内启动染色体重排的抑制剂和通过骨髓中 MLL-AF9 基因组重排的存在来测量 AF9 基因外周血。这些在离体细胞培养和体内小鼠模型中的独特方法将为潜在致癌染色体重排的启动提供重要见解白血病发生。解开易位的病因和后果可能会带来新的结果治疗和预防的方法。