Role of LMO1 in Neuroblastoma Initiation and Maintenance

LMO1 在神经母细胞瘤发生和维持中的作用

• 批准号: 9032459
• 负责人: A. THOMAS LOOK
• 金额: $ 60.68万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-01 至 2020-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9032459
• 关键词: Accounting; Address; Advanced Development; Binding Sites; Biological Assay; Biological Models; Cell model; Cells; Cessation of life; Characteristics; Child; Clonal Evolution; Complement; DNA; DNA Resequencing; Data; Dependence; Development; Disease; Dissection; Doxycycline; Enhancers; Epigenetic Process; Event; Genes; Genetic; Genetic Determinism; Genetic Enhancer Element; Genetic Polymorphism; Goals; Growth; Health; Human; Inherited; Introns; Investigation; LIM Domain; Laboratories; Leadership; MYCN gene; Maintenance; Malignant - descriptor; Malignant Childhood Neoplasm; Malignant Neoplasms; Mediating; Methods; Mission; Modeling; Molecular; Molecular Target; Mutation; Neuroblastoma; Oncogenes; Oncogenic; Outcome; Pathway interactions; Penetrance; Peripheral; Phenotype; Predisposition; Principal Investigator; Proteins; Public Health; Publishing; Recurrence; Regulatory Element; Reporter; Research; Research Project Grants; Resources; Role; Single Nucleotide Polymorphism; Site; Somatic Mutation; Susceptibility Gene; Sympathetic Nervous System; Testing; Tissues; Transgenic Organisms; Treatment Failure; United States National Institutes of Health; Up-Regulation; Validation; Variant; Work; Zebrafish; anticancer research; base; cancer genome; cancer initiation; cell growth; chemotherapy; childhood cancer mortality; clinically relevant; cofactor; design; evidence base; functional genomics; genetic approach; genetic association; genome editing; genome wide association study; high risk; human disease; in vivo; induced pluripotent stem cell; innovation; insight; malignant phenotype; molecular phenotype; molecular subtypes; neoplastic cell; nervous system development; neuroblastoma cell; novel; novel therapeutics; overexpression; personalized therapeutic; programs; public health relevance; self-renewal; skills; transcription factor; tumor; tumor DNA; tumorigenesis

 DESCRIPTION (provided by applicant): Children with disseminated neuroblastoma have a very high risk of treatment failure and death despite receiving greatly intensified chemotherapy, underscoring the need to design novel molecular therapies for this disease, which constitutes the long-term goal of our proposal. However, recent efforts to discover promising molecular targets in this aggressive pediatric malignancy have revealed a very low somatic mutation rate, and the majority of high-risk tumors do not harbor druggable oncogenic proteins activated by somatic mutations, demonstrating that personalized therapeutic strategies will require insights well beyond those afforded by resequencing tumor DNA alone. This multiple principal investigator project will build on our recent genome- wide association study (GWAS) discovery of a robust genetic association at the LMO1 gene locus, which encodes a LIM-domain-only (LMO) transcriptional cofactor. Together, our published and unpublished preliminary data support a major oncogenic role for LMO1 in the most aggressive subset of neuroblastomas, and suggest the following central hypothesis: LMO1 is required for the initiation and maintenance of the malignant phenotype in a substantial subset of high-risk neuroblastoma cases. We propose to test this original concept in two integrated Specific Aims using the multi-PI leadership mechanism to bring together complementary research skills and resources available in the Maris and Look laboratories. In Aim 1, we will focus on how polymorphisms at the LMO1 locus alter regulatory mechanisms of the LMO1 gene in developing sympathetic nervous system cells to promote the initiation of neuroblastoma using genetic and epigenetic approaches in human-derived tissues and genome editing in the zebrafish model system. In Aim 2, we will focus on the mechanism by which LMO1 overexpression is somatically deregulated during malignant neuroblastic clonal evolution, and will seek to discover the key cellular networks that maintain the highly proliferative and metastatic phenotype characteristic of neuroblastomas high levels of LMO1 expression. The innovation of this project resides in the combined use of robust human (epi)genetic approaches with a novel and highly manipulable zebrafish model of neuroblastoma to address a fundamental problem with high clinical relevance. Our results will establish the requirement for LMO1 in neuroblastoma initiation, growth and survival. The work proposed here will serve as a roadmap for the investigation of GWAS discoveries in cancer and other human diseases, providing a paradigm for determining their mechanistic and clinical relevance.

 描述（由适用提供）：具有传播神经母细胞瘤的儿童的治疗失败风险很高，死亡目的地接受了大量强烈的化学疗法，强调了为该疾病设计新型分子疗法的必要性，这构成了我们建议的长期目标。然而，最近在这种侵略性的小儿恶性肿瘤中发现承诺分子靶标的努力表明，体细胞突变率非常低，大多数高风险肿瘤并不含有可吸毒的致癌蛋白质被体细胞突变激活，这表明个性化的治疗策略将需要远远超出人们对单独依赖的tumor tumor dna dna的良好负担的洞察力。这个多个主要研究者项目将基于我们最近全基因组关联研究（GWAS）在LMO1基因基因座的稳健遗传关联的发现，该基因座编码仅LIM域（LMO）转录辅助因子。总之，我们发表的未发表的初步数据支持LMO1在最激进的神经细胞瘤子集中的主要致癌作用，并提出了以下中心假设：LMO1是在高风险神经细胞瘤的大量子集中对恶性表型的主动和维持恶性表型的主动性和维持所必需的。我们建议使用多PI领导力机制在两个集成的特定目标中测试这一原始概念，以将Maris中可用的完全研究技能和资源汇总在一起，并寻找实验室。在AIM 1中，我们将重点关注LMO1基因座的多态性如何改变LMO1基因的调节机制，以开发交感神经系统细胞，以使用人类衍生的组织中的遗传和表观遗传学方法在Zebrafish模型系统中使用遗传和表观遗传方法促进神经细胞瘤的启动。在AIM 2中，我们将重点关注LMO1在恶性神经母细胞瘤中体外进行过表达的机制，并将试图发现维持高度增殖和转移性表型的关键细胞网络的神经细胞高水平表型LMO1表达的高水平。该项目的创新属于强大的人（EPI）遗传方法的联合使用，以及一种新颖且高度可操纵的神经母细胞瘤模型，以解决具有高临床相关性的基本问题。我们的结果将确定在神经母细胞瘤倡议，生长和生存中对LMO1的要求。这里提出的工作将作为研究癌症和其他人类疾病发现GWAS发现的路线图，从而提供了确定其机械和临床相关性的范例。