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（改编自研究者摘要）：儿童期病因 白血病目前正在进行大规模流行病学研究， 美国和英国。研究者建议检查 儿童急性淋巴细胞性白血病和 急性髓细胞白血病（ALL和AML），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，在大多数情况下， 儿童白血病，t（12;21）（或TEL-AML 1基因融合）可在出生前发生 在一小部分后来发展为儿童白血病的个体中。这些 研究将扩大并扩展到一个独立的人群， 加州。约150例具有特定畸变的患者，包括t（12;21）， t（1;19）、t（8;21）和NRAS突变将通过筛选以下突变进行“回溯”： 新生儿足跟刺古特里点的畸变， 出生畸变将首先在基因组DNA水平上表征， 然后将其作为克隆型标记用于敏感的筛选试验， 古特里斑点。 除了用作白血病细胞克隆的标记物外，易位 融合序列提供了对形成融合的过程的洞察。 TEL-AML 1融合连接倾向于分组为“微簇”，或不同的 较大内含子断裂点簇区域内的区域。的 微簇独立于嵌合致癌基因的结构， 蛋白质，这对所有患者都是一样的。中断点的微聚类 某些区域表明内在DNA序列或染色质的特征 结构在易位形成的过程中是关键的。这些 特征将通过基于统计的DNA序列识别工具进行探测 沿着协同的实验室分析以鉴定序列基序。一 该项目的最终目标是开发灵敏地跟踪白血病的方法 克隆在治疗的病人，以衡量治疗的成功。在 总之，本项目旨在阐明遗传的时间和结构， 导致儿童白血病的事件。