ANALYSIS OF MLL TRANSLOCATIONS AND FUSION GENES

MLL 易位和融合基因分析

• 批准号: 7725119
• 负责人: HEIDI G SUPER
• 金额: $ 6.03万
• 依托单位: UNIVERSITY OF NORTH DAKOTA
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-05-01 至 2009-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7725119
• 关键词: Binding; Biological Assay; Cell Line; Chromosome Breakage; Chromosomes; Computer Retrieval of Information on Scientific Projects Database; DNA Sequence Rearrangement; DNA topoisomerase II alpha; DNA topoisomerase II binding protein; DNA-Binding Proteins; Down-Regulation; Funding; Gene Expression; Gene Expression Regulation; Gene Proteins; Genes; Genomics; Goals; Grant; Health; Human; Institution; Link; MLL gene; Methods; Molecular Genetics; Oncogenes; Pathway interactions; Proteins; RNA Interference; Research; Research Personnel; Research Proposals; Resources; Role; Source; Stream; Testing; Therapeutic; Topoisomerase II; United States National Institutes of Health; base; cancer cell; cell growth; fusion gene; leukemia; leukemogenesis; novel strategies; research study

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The focus of this research proposal is continued study of the MLL gene, which undergoes frequent rearrangement with various chromosomal regions, resulting in leukemogenic MLL fusion genes. One long term objective is to understand the mechanism of chromosome breakage and rearrangement of MLL and its translocation partner genes. The experimental approaches used to study this mechanism are based on the hypothesis that specific proteins act aberrantly within the MLL gene facilitating union of non-homologous genomic regions. One such protein, DNA topoisomerase II has been strongly linked to MLL breaks, but has not been shown to bind directly in the MLL breakpoint region. The experiments described include two assays to show direct binding of proteins (DNA topoisomerase II or as yet unidentified proteins within the MLL breakpoint region. A second goal of the proposed research is to study the role of the MLL fusion genes/proteins in leukemogenesis. We will take a novel approach of using RNA interference to specifically down regulate MLL fusion genes in leukemia cell lines. The goals of these experiments are to 1: test a new and possibly long term method for down regulation of oncogenes in cancer cells and 2: to analyze the down stream effects of fusion gene regulation on cell growth and gene expression. The research proposed within is directly related to human health issues. Identification of molecular interactions of genomic regions of MLL and DNA binding proteins will be important in understanding the mechanism of leukemogenic chromosome rearrangements involving MLL. The RNA interference studies serve to give a better understanding of the molecular genetic pathway of leukemogenesis, and more importantly have potential as a oncogene specific therapeutic approach.

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 这项研究计划的重点是继续研究MLL基因，该基因经历了频繁的重排与各种染色体区域，导致白血病MLL融合基因。 一个长期的目标是了解MLL及其易位伴侣基因的染色体断裂和重排的机制。 用于研究这种机制的实验方法是基于这样的假设，即特定的蛋白质在MLL基因内异常地起作用，从而促进非同源基因组区域的结合。 一种这样的蛋白质，DNA拓扑异构酶II已经与MLL断裂强烈相关，但尚未显示直接结合在MLL断裂点区域。 所描述的实验包括两种测定，以显示蛋白质（DNA拓扑异构酶II或MLL断裂点区域内尚未鉴定的蛋白质）的直接结合。 拟议研究的第二个目标是研究MLL融合基因/蛋白在白血病发生中的作用。我们将采取一种新的方法，使用RNA干扰特异性下调白血病细胞系中的MLL融合基因。 这些实验的目的是：1：测试一种新的和可能长期的方法，下调癌细胞中的癌基因和2：分析融合基因调控对细胞生长和基因表达的下游影响。 其中提出的研究与人类健康问题直接相关。 MLL基因组区域与DNA结合蛋白分子相互作用的鉴定对于理解MLL致白血病染色体重排的机制具有重要意义。RNA干扰研究有助于更好地理解白血病发生的分子遗传学途径，更重要的是，它具有作为癌基因特异性治疗方法的潜力。