BACKTRACKING TRANSLOCATIONS IN CHILDHOOD LEUKEMIA

儿童白血病的回溯易位

• 批准号: 6514802
• 负责人: Joseph Leo Wiemels
• 金额: $ 25.08万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-03-02 至 2004-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6514802
• 关键词: DNA gyrase; acute lymphocytic leukemia; acute myelogenous leukemia; adolescence (12-20); binding sites; child (0-11); chromatin; chromosome translocation; computer assisted sequence analysis; computer system design /evaluation; disease /disorder etiology; enzyme activity; fusion gene; genetic markers; human tissue; introns; mathematical model; minimal residual disease; neoplasm /cancer genetics; nucleoproteins; pediatric neoplasm /cancer; polymerase chain reaction

DESCRIPTION (Adapted from investigator's abstract): The etiology of childhood leukemia is currently being examined under large-scale epidemiology studies in the US and UK. The investigator proposes to examine the timing and etiology of the most frequent genetic aberrations in childhood acute lymphoblastic and myeloblastic leukemia (ALL and AML) by using molecular biology and bioinformatic tools and resources in patient diagnostic and archived materials. The investigator has previously shown that the most common translocation in childhood leukemia, t(12;21) (or TEL-AML1 gene fusion) can occur before birth in a small number of individuals who later developed childhood leukemia. These studies will be expanded and extended to an independent population in California. About 150 patients with specific aberrations, including t(12;21), t(1;19), t(8;21), and NRAS mutations, will be "backtracked" by screening for the aberration in the neonatal heel-prick Guthrie spots that were taken at birth. The aberrations will first be characterized at the genomic DNA level, and then will be used as clonotypic markers in sensitive screening assays of Guthrie spots. In addition to this use as markers of leukemia cell clones, translocation fusion sequences provide insight into the processes that formed the fusion. TEL-AML1 fusion junctions tend to group into "micro-clusters," or distinct regions within the larger intronic breakpoint cluster regions. The micro-clustering is independent of the structure of the chimeric oncogenic protein, which is the same for all patients. Micro-clustering of breakpoints in certain areas suggests that features of the intrinsic DNA sequence or chromatin structure are critical in the process of formation of the translocation. These features will be probed by statistically based DNA sequence recognition tools along with a coordinated laboratory analysis to identify sequence motifs. A final goal of the project is to develop methods to sensitively track leukemia clones in treated patients in order to gauge the success of therapy. In summary, this project aims to elucidate the timing and structure of the genetic events that lead to childhood leukemia.

描述（改编自调查员的摘要）：童年的病因 目前正在大规模流行病学研究中检查白血病 美国和英国。研究人员建议检查 儿童急性淋巴细胞中最常见的遗传畸变和 通过使用分子生物学和 患者诊断和存档材料中的生物信息学工具和资源。 研究人员先前已经表明，最常见的易位 儿童白血病，T（12; 21）（或Tel-AML1基因融合）可能发生在出生前 在少数人后来患有童年白血病的人中。这些 研究将扩展并扩展到独立人群 加利福尼亚。大约150例特异性畸变患者，包括T（12; 21）， t（1; 19），t（8; 21）和NRAS突变将通过筛查“回溯” 新生儿脚后跟prick斑点的畸变被拍摄 出生。畸变将首先在基因组DNA水平上进行表征， 然后将用作敏感筛选测定法中的clonotypic标记 Guthrie景点。 除了用作白血病细胞克隆标记的这种用途外，易位 融合序列可洞悉形成融合的过程。 Tel-AML1融合连接倾向于将“微群体”分组为或不同 较大的内含子断点群集区域内的区域。这 微聚类与嵌合致癌的结构无关 蛋白质，对所有患者都是相同的。断点的微簇 某些区域表明固有DNA序列或染色质的特征 结构在易位形成过程中至关重要。这些 功能将通过基于统计的DNA序列识别工具来探测 以及协调的实验室分析以识别序列基序。一个 该项目的最终目标是开发敏感追踪白血病的方法 治疗患者的克隆以评估治疗的成功。在 总结，该项目旨在阐明遗传的时间和结构 导致儿童白血病的事件。