Role of LMO1 in Neuroblastoma Initiation and Maintenance

 描述（由申请人提供）：尽管接受了大大强化的化疗，但患有播散性神经母细胞瘤的儿童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揭示了非常低的体细胞突变率，并且大多数高风险肿瘤不具有由体细胞突变激活的可药物化致癌蛋白，这表明个性化治疗策略需要远远超出单独重新测序肿瘤DNA所提供的见解。这个多个主要研究者项目将建立在我们最近的全基因组关联研究（GWAS）发现的LMO 1基因位点的强大遗传关联的基础上，该基因位点编码一个仅LIM结构域（LMO）转录辅因子。总之，我们已发表和未发表的初步数据支持LMO1在最具侵袭性的神经母细胞瘤亚群中的主要致癌作用，并提出以下中心假设：LMO1是高风险神经母细胞瘤病例中大量亚群恶性表型的启动和维持所必需的。我们建议使用多PI领导机制在两个集成的具体目标中测试这一原始概念，以汇集Maris和Look实验室中的互补研究技能和资源。在目标1中，我们将重点关注LMO1基因座的多态性如何改变LMO1基因在交感神经系统细胞发育中的调控机制，以促进在人类来源的组织中使用遗传和表观遗传方法以及在斑马鱼模型系统中进行基因组编辑来启动神经母细胞瘤。在目标2中，我们将重点关注LMO1过表达在恶性成神经细胞克隆进化过程中体细胞失调的机制，并将寻求发现维持成神经细胞瘤高水平LMO1表达的高度增殖和转移表型特征的关键细胞网络。该项目的创新在于将强大的人类（epi）遗传方法与新型且高度可操作的神经母细胞瘤斑马鱼模型相结合，以解决具有高度临床相关性的基本问题。我们的研究结果将建立LMO1在神经母细胞瘤的发生，生长和生存的要求。本文提出的工作将作为研究GWAS在癌症和其他人类疾病中的发现的路线图，为确定其机制和临床相关性提供范例。

 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 Together, our published and unpublished preliminary data support a major oncogenic role for LMO1 in the most aggressive subset of neuroblastomas, and suggest the following central hypothesis: LMO1 is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.