Identifying and targeting oncogenic Myc enhancer control in pediatric tumors

识别和靶向儿童肿瘤中的致癌 Myc 增强子控制

• 批准号: 9544393
• 负责人: Charles Yang Lin
• 金额: $ 1.43万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9544393
• 关键词: Aggressive behavior; Amplifiers; Binding; Biological Models; Cell Line; Cell Nucleus; Cells; Chemicals; Childhood; Chromatin; Clinical; Complex; Consensus; Data; Dependency; Disease; Distal; E-Box Elements; Elements; Enhancers; Euchromatin; Family; Gene Expression; Gene Targeting; Genes; Genetic; Genetic Enhancer Element; Genetic Transcription; Genome; Genomic DNA; Genomics; Housekeeping; Human; In Vitro; Invaded; Investigation; Length; Link; MYC Family Protein; MYCL1 gene; MYCN gene; Malignant Neoplasms; Maps; Mediating; Mediator of activation protein; Modeling; Mus; Neoplasm Metastasis; Neuroblastoma; Oncogenic; Output; Pathway interactions; Pediatric Neoplasm; Pharmacology; Physiological; Primary Neoplasm; Property; Proto-Oncogene Proteins c-myc; Regulation; Role; Route; Shapes; Specific qualifier value; Structure; TWIST1 gene; Testing; Therapeutic; Tissue-Specific Gene Expression; Tissues; To specify; Transcriptional Regulation; Validation; Work; chemical genetics; computer framework; disorder risk; genetic approach; genetic signature; high risk; in vivo; in vivo Model; member; mouse model; neoplastic cell; novel; novel strategies; osteosarcoma; programs; promoter; response; targeted treatment; therapeutic target; transcription factor; tumor; tumor progression

Myc deregulation is a hallmark of cancer and promotes tumor aggression across multiple tumor types. When deregulated, levels of the full length Myc (MYC, MYCN, or MYCL) transcription factor are drastically increased, leading to a global remodeling of gene expression that is poorly understood. Here we show evidence for and propose “Myc enhancer invasion” as a novel mechanism in which excess Myc protein invades distal cis-regulatory enhancers that are not normally bound at physiological Myc levels. As enhancers control tissue specific gene expression, Myc invasion creates aberrant regulatory interactions that drive tumor progression and can be targeted as a therapeutic strategy. Specifically, we have developed and provide evidence for a model of Myc enhancer invasion in which 1) a subset of enhancers contain weak Myc binding motifs that are accessed when Myc is deregulated. 2) Invaded enhancers act as reservoirs for excess Myc binding and drive the Myc responsive transcription of target genes. 3) Tumor specific enhancer landscapes specify the context of Myc enhancer invasion leading to different enhancer invasion responsive genes in different tumors. 4) Enhancer invaded pathways and other transcription factors that form enhancers can be targeted to interdict tumor specific Myc transcriptional control. To investigate this model for Myc enhancer invasion, we propose the following specific aims. 1) To map and model Myc enhancer invasion in neuroblastoma and osteosarcoma in order to identify genomic parameters that predicate enhancer invasion. 2) To investigate transcriptional consequences of Myc enhancer invasion in vitro and in vivo in order to functionally validate that tumor specific Myc enhancer invaded target genes are dynamically and selectively responsive to Myc perturbation. 3) To identify and target oncogenic Myc enhancer regulation to establish proof of concept for the therapeutic targeting of Myc enhancer regulation. We will perform this work in pediatric neuroblastoma and osteosarcoma models and primary tumors. In these diseases, Myc deregulation is associated with high risk disease, metastasis, increased tumor aggression, and poor responsiveness to existing treatments. As no targeted therapies exist for Myc deregulated neuroblastoma or osteosarcoma, there is a critical unmet need for novel strategies to identify dependencies and effectors of Myc deregulation. In our preliminary data, we find that the enhancer transcription factor TWIST1 acts as a co-factor of MYCN enhancer invasion and is a specific dependency of MYCN driven neuroblastoma. These data highlight the utility of the proposed approach to connect mechanistic investigation of Myc transcriptional regulation to novel frameworks for the identification and validation of tumor specific therapeutic targets in Myc driven neuroblastoma and osteosarcoma.

MYC放松管制是癌症的标志，可促进多种肿瘤类型的肿瘤侵略性。 放松管制时，全长MYC（MYC，MYCN或MYCL）的转录因子急剧是 增加，导致对基因表达的全球重塑，这是鲜为人知的。我们在这里显示 证据和建议“ MYC增强子入侵”是一种超过MYC蛋白的新机制 入侵通常不在物理MYC水平上的远端顺式调节增强剂。作为增强剂 控制组织特异性基因表达，MYC侵袭会产生异常的调节相互作用，使肿瘤驱动肿瘤 进展，可以作为治疗策略作为目标。 具体而言，我们已经为MYC增强子入侵的模型开发并提供了证据 1）增强器的子集包含弱MYC结合基序，这些基序被误管了。 2） 入侵的增强剂充当过度MYC绑定的储层，并驱动MYC的反应性转录 靶基因。 3）肿瘤特异性增强子景观指定MYC增强子入侵的背景 不同肿瘤中不同增强子侵袭反应性基因。 4）增强子入侵途径和其他 形成增强子的转录因子可以针对阻止肿瘤特异性MYC转录控制。 为了调查MYC增强子入侵的模型，我们提出了以下特定目标。 1）映射 以及在神经母细胞瘤和骨肉瘤中的MYC增强子侵袭，以鉴定基因组 鉴定增强子入侵的参数。 2）研究MYC增强器的转录后果 在体外和体内侵袭，以便在功能上验证特定于肿瘤的MYC增强子入侵目标 基因在动态和选择性地响应MYC扰动。 3）识别和靶向致癌MYC 增强剂调节以建立概念验证MYC增强子调节的治疗靶向。 我们将在小儿神经母细胞瘤和骨肉瘤模型和原发性肿瘤中进行这项工作。在 这些疾病，MYC放松管制与高风险疾病，转移，肿瘤增加有关 侵略性，对现有治疗的反应不良。由于MYC不存在目标疗法 放松管制的神经母细胞瘤或骨肉瘤，对识别的新型策略有一个至关重要的未满足的需求 MYC放松管制的依赖性和影响。在我们的初步数据中，我们发现增强剂 转录因子Twist1充当MyCN增强子入侵的共同因素，是特定的依赖性 MYCN驱动神经母细胞瘤。这些数据突出了所提出的连接机械方法的实用性 对肿瘤鉴定和验证的新型框架的MYC转录调节的研究 MYC驱动的神经母细胞瘤和骨肉瘤中的特定治疗靶标。