Etiology of translocations in hematopoietic cells

造血细胞易位的病因学

• 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
• 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

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特定于造血细胞的 修复DNA损伤，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 软组织肉瘤。DSB是高度重组的，增加了相互之间的信息交换 两个同源DNA双链体相差几个数量级；因此，哺乳动物细胞有可能 在DSB修复过程中出现重新安排的风险。暴露于空气中的染色体DSB 放射、烷化剂和拓扑异构酶II(TopoII)抑制剂是 人类癌症的治疗。包含TopoII抑制剂依托泊苷的治疗方案如下 与一类治疗相关的急性髓系白血病(t-AML)和染色体相关 染色体11q23带上涉及混合系白血病(MLL)基因的易位。 T-AML和婴儿白血病中11q23 MLL断裂点的相似性表明 新生婴儿白血病和宫内暴露于TopoII抑制剂。潜在的TOPO II抑制剂名单 是广泛存在的，目前尚不清楚这些化合物中哪些有直接潜在的诱导 临床环境中观察到的染色体易位。使用独特的遗传系统 确定11q23 MLL基因断裂点簇区内双链断裂的修复潜力 和共同的伴侣基因导致染色体易位，这一提议将确定(1) 暴露于TopoII抑制剂以启动细胞内染色体重排的可能性 MLL和AF9基因的断裂点聚集区与临床中观察到的相似； 以及(2)建立靶向小鼠模型以在体内确定暴露于TopoII的可能性 在MLL的断点簇区内启动染色体重排的抑制剂和 通过骨髓和骨髓中存在MLL-AF9基因组重排来检测AF9基因 外周血液。这些在体外细胞培养和体内小鼠模型中的独特方法将 对潜在致癌的染色体重排的启动和 白血病的发生。解开易位的病因和后果可能会带来新的 治疗和预防的方法。