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失调是癌症的标志，并促进多种肿瘤类型的肿瘤侵袭。 当去调控时，全长Myc（MYC、MYCN或MYCL）转录因子的水平急剧降低， 增加，导致基因表达的整体重塑，这是知之甚少。在此我们表明 证据并提出“Myc增强子入侵”作为一种新的机制，其中过量的Myc蛋白 侵入在生理Myc水平下通常不结合的远端顺式调节增强子。例如增强子 控制组织特异性基因表达，Myc入侵产生异常的调节相互作用， 进展，并且可以作为治疗策略靶向。 具体来说，我们已经开发了Myc增强子入侵模型并提供了证据，其中 1)增强子的一个子集含有弱Myc结合基序，当Myc被去调节时，所述基序被接近。（二） 侵入的增强子充当过量Myc结合的储库，并驱动Myc应答转录， 靶基因3)肿瘤特异性增强子景观指定Myc增强子侵入的背景，导致 不同肿瘤中不同的增强子侵袭应答基因。4)增强子侵入途径和其他 可以靶向形成增强子的转录因子以阻断肿瘤特异性Myc转录控制。 为了研究Myc增强子入侵的这种模型，我们提出了以下具体目标。1)映射 并在神经母细胞瘤和骨肉瘤中建立Myc增强子侵袭模型，以鉴定基因组 预测增强子入侵的参数。2)研究Myc增强子的转录影响 体外和体内侵袭，以便功能性地验证肿瘤特异性Myc增强子侵袭靶 基因对Myc扰动动态地和选择性地响应。3)识别和靶向致癌Myc 增强子调控的研究，以建立Myc增强子调控的治疗靶向的概念验证。 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 在这些疾病中，Myc失调与高风险疾病、转移、肿瘤增加相关。 攻击性，以及对现有治疗的反应性差。由于没有针对Myc的靶向疗法 神经母细胞瘤或骨肉瘤，有一个关键的未满足的需要，新的战略，以确定 Myc失调的依赖性和效应物。在我们的初步数据中，我们发现增强子 转录因子TWIST 1作为MYCN增强子侵入的辅助因子，是MYCN增强子侵入的特异性依赖性因子。 MYCN驱动的神经母细胞瘤。这些数据突出了所提出的方法的实用性，以连接机械 Myc转录调控的研究，以鉴定和验证肿瘤的新框架 Myc驱动的神经母细胞瘤和骨肉瘤中的特异性治疗靶点。