Etiology of translocations in hematopoietic cells

项目摘要： 我研究的长期目标是了解造血特异性 修复DNA损伤的发展计划，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具有高度重组性，增加了基因组之间的信息交换。 两个同源的DNA双链体的数量级;因此，哺乳动物细胞是潜在的 在DSB维修期间发生的重新安排风险。暴露于以下物质后的染色体DSB结果 辐射、烷化剂和拓扑异构酶II（topoII）抑制剂，它们是 人类癌症的治疗包括topoII抑制剂依托泊苷的治疗方案是 与一类治疗相关的急性髓性白血病（t-AML）和染色体 涉及染色体带11 q23上的混合谱系白血病（MLL）基因的易位。 t-AML和婴儿白血病中11 q23 MLL断裂点的相似性表明， 新生儿白血病和宫内暴露于topoII抑制剂。潜在的拓扑异构酶II抑制剂列表 是广泛的，目前尚不清楚这些化合物中的哪一种具有直接诱导 在临床环境中观察到的染色体易位。利用独特的基因系统 确定11 q23 MLL基因断裂点簇区域内DSB的修复潜力 和共同的伴侣基因导致染色体易位，这一建议将（1）确定 暴露于topoII抑制剂以启动细胞内染色体重排的可能性 MLL和AF 9基因的断裂点簇区域与临床环境中观察到的相似; 和（2）建立靶向小鼠模型以确定体内暴露于topoII的可能性 在MLL的断裂点簇区内引发染色体重排的抑制剂，和 通过骨髓中MLL-AF 9基因组重排的存在测量的AF 9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 对潜在致癌染色体重排的启动提供了重要的见解， 白血病发生解开易位的病因和后果可能会导致新的 治疗和预防的方法。

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.