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（由申请人提供）：尽管接受了极大强化的化疗，患有播散性神经母细胞瘤的儿童仍具有非常高的治疗失败和死亡风险，这强调了为这种疾病设计新型分子疗法的必要性，这构成了我们提案的长期目标。然而，最近在这种侵袭性儿科恶性肿瘤中发现有希望的分子靶点的努力表明，体细胞突变率非常低，并且大多数高风险肿瘤不含有由体细胞突变激活的可药物致癌蛋白，证明个性化治疗策略需要的见解远远超出仅对肿瘤 DNA 进行重测序所提供的见解。这个多位首席研究员项目将建立在我们最近的全基因组关联研究 (GWAS) 的基础上，该研究发现 LMO1 基因位点存在强大的遗传关联。我们已发表和未发表的初步数据共同支持 LMO1 在最具侵袭性的神经母细胞瘤亚型中的主要致癌作用，并提出以下中心假设：LMO1。在大量高风险神经母细胞瘤病例中，恶性表型的启动和维持是必需的，我们建议使用多 PI 领导机制将互补的研究技能和可用资源结合在一起，在两个综合具体目标中测试这一原始概念。在 Maris 和 Look 实验室中，我们将重点研究 LMO1 位点的多态性如何改变 LMO1 基因在发育交感神经系统细胞中的调节机制，以利用遗传和表观遗传促进神经母细胞瘤的发生。在目标 2 中，我们将重点研究 LMO1 过度表达在恶性神经母细胞克隆进化过程中体细胞失调的机制，并寻求发现维持 LMO1 过度表达的关键细胞网络。神经母细胞瘤的高度增殖和转移表型特征高水平的 LMO1 表达该项目的创新在于将强大的人类（表观）遗传学方法与新颖且高度可操作的方法相结合。我们的研究结果将确定 LMO1 在神经母细胞瘤发生、生长和存活中的要求，以解决神经母细胞瘤的斑马鱼模型，为癌症和其他人类的 GWAS 研究发现提供路线图。疾病，为确定其机制和临床相关性提供了范例。