Molecular Targeting of MLL and Associated Factors

MLL 的分子靶向及相关因素

基本信息

批准号：
7624715
负责人：
MICHAEL L CLEARY
金额：
$ 29.57万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-08-05 至 2010-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7624715
关键词：
Address Adult Affect Biochemical Biochemical Pathway Biological Models Cell Line Child Chimeric Proteins Chromosomal translocation Clinical Code Complex Family Gene Expression Genetic Human Infant Link MLL gene MLLT2 gene Maintenance Mediating Menin Methyltransferase Modeling Molecular Molecular Target Morbidity - disease rate Mutate Mutation Myeloid-Lymphoid Leukemia Protein Nature Oncogene Proteins Oncogenic Outcome Pathway interactions Patients Phenocopy Physiological Play Proteins Proto-Oncogenes Research Personnel Role Therapeutic Transcriptional Regulation Treatment Protocols Tumor Suppressor Genes Tumor Suppressor Proteins alpha-Thalassemia base genetic analysis histone methyltransferase inhibitor/antagonist intermolecular interaction leukemia leukemogenesis mortality mutant novel outcome forecast pre-clinical programs protein complex response small molecule standard care therapeutic target

项目摘要

DESCRIPTION (provided by applicant): The Mixed Lineage Leukemia (MLL) gene codes for a histone methylase, which is frequently mutated by chromosomal translocations in human leukemias associated with a poor clinical outcome. The studies proposed in this application address the hypothesis that the leukemogenic actions of MLL oncoproteins are critically dependent on proteins recently discovered to associate with MLL or its fusion partners, and that the activities or interactions of these associated factors constitute potential targets for molecular therapies. This hypothesis is based on substantial preliminary studies that have resulted in the purification of multi-protein complexes containing MLL or its major fusion partners, and identification of proteins that associate with wild type and/or mutant MLL proteins. One of the recently identified MLL-associated proteins is menin, a product of the MEN1 tumor suppressor gene. Menin is an essential component of the MLL complex, is required for maintenance of Hox gene expression, and also interacts with oncogenic MLL fusion proteins. Studies in the first specific aim will determine the role of menin in the initiation and maintenance of MLL-mediated leukemogenesis using genetic approaches in pre-clinical and cell line transformation model systems. These studies will also establish the feasibility of targeting MLL-menin interactions as a molecular therapeutic strategy. Studies in the second aim will employ genetic and biochemical approaches to identify additional unknown factors that interact with transformation critical domains of MLL, establish their specific roles in leukemogenesis, and determine their feasibility as molecular therapeutic targets. Studies in the third specific aim are based on our discovery of an AF4 multi-protein complex that contains among other proteins the MLL fusion partner ENL. This novel complex links the two major families of MLL fusion partners on a common biochemical pathway. These observations will be extended by further characterizing the molecular nature of the AF4/ENL pathway, determining its implications for transcriptional regulation in general, and establishing its role in MLL-mediated leukemogenesis. The therapeutic value of targeting the activities or interactions of AF4 complex components with pathogenic roles in MLL leukemias will be interrogated using preclinical transformation models.

描述（由申请人提供）：混合谱系白血病（MLL）基因编码组蛋白甲基化酶，该酶经常因与不良临床结果相关的人类白血病中的染色体易位而突变。本申请中提出的研究提出了这样的假设：MLL癌蛋白的致白血病作用严重依赖于最近发现的与MLL或其融合伙伴相关的蛋白质，并且这些相关因子的活性或相互作用构成了分子治疗的潜在靶标。该假设基于大量的初步研究，这些研究导致了含有 MLL 或其主要融合伴侣的多蛋白复合物的纯化，以及与野生型和/或突变 MLL 蛋白相关的蛋白的鉴定。最近发现的 MLL 相关蛋白之一是 menin，它是 MEN1 肿瘤抑制基因的产物。 Menin 是 MLL 复合体的重要组成部分，是维持 Hox 基因表达所必需的，并且还与致癌 MLL 融合蛋白相互作用。第一个具体目标的研究将利用临床前和细胞系转化模型系统中的遗传方法确定 menin 在 MLL 介导的白血病发生的启动和维持中的作用。这些研究还将确定以 MLL-menin 相互作用为目标的分子治疗策略的可行性。第二个目标的研究将采用遗传和生化方法来识别与 MLL 转化关键域相互作用的其他未知因子，确定它们在白血病发生中的特定作用，并确定它们作为分子治疗靶点的可行性。第三个具体目标的研究基于我们对 AF4 多蛋白复合物的发现，该复合物除其他蛋白外还含有 MLL 融合伙伴 ENL。这种新颖的复合物通过共同的生化途径将 MLL 融合伙伴的两个主要家族连接起来。这些观察结果将通过进一步表征 AF4/ENL 途径的分子性质、确定其对一般转录调控的影响以及确定其在 MLL 介导的白血病发生中的作用来扩展。将使用临床前转化模型来探讨针对 AF4 复合物成分的活性或相互作用与 MLL 白血病致病作用的治疗价值。