Identifying and targeting oncogenic Myc enhancer control in pediatric tumors

MYC去调控是癌症的一个标志，并促进多种肿瘤类型的肿瘤侵袭性。 当解除调控时，全长Myc(MYC、MYCN或MYCL)转录因子的水平急剧下降 增加，导致基因表达的全球重塑，但人们对此知之甚少。我们在这里展示 “Myc增强子侵袭”是过量Myc蛋白的一种新机制 侵入通常不结合在生理Myc水平的远端顺式调节增强子。作为增强剂 控制组织特异性基因表达，Myc侵袭产生异常的调控相互作用，从而推动肿瘤 进展，并可作为一种治疗策略。 具体地说，我们已经开发并提供了Myc增强子侵袭模型的证据 1)一组增强子包含弱的Myc结合基序，当Myc被解除调控时可以访问这些基序。2) 侵袭的增强子作为过量Myc结合的储存库，并推动Myc应答转录 靶基因。3)肿瘤特异性增强子景观规定了Myc增强子入侵的背景，导致 不同肿瘤中不同的增强子侵袭反应基因。4)增强者入侵路径和其他 形成增强子的转录因子可以靶向阻断肿瘤特异性Myc转录调控。 为了研究Myc增强子侵袭的这一模型，我们提出了以下具体目标。1)映射 和模型Myc增强子在神经母细胞瘤和骨肉瘤中的侵袭以确定基因组 预测增强子入侵的参数。2)研究Myc增强子的转录结果 为了从功能上验证肿瘤特异性Myc增强子侵袭靶点 基因对Myc的扰动有动态和选择性的反应。3)识别和靶向致癌Myc 增强子调控为Myc增强子调控的治疗靶向建立概念证据。 我们将在儿童神经母细胞瘤、骨肉瘤模型和原发肿瘤中进行这项工作。在……里面 这些疾病中，Myc基因的缺失与高危疾病、转移、肿瘤增加有关 攻击性强，对现有治疗反应差。由于没有针对Myc的靶向治疗 放松管制的神经母细胞瘤或骨肉瘤，迫切需要新的策略来识别 Myc放松管制的依存性和效应者。在我们的初步数据中，我们发现增强剂 转录因子Twist1是MYCN增强子侵袭的辅助因子，是MYCN增强子侵袭的特异性依赖因子 由MYCN引起的神经母细胞瘤。这些数据突出了所提出的连接机械设备的方法的实用性 Myc转录调控对肿瘤识别和验证新框架的研究 Myc驱动的神经母细胞瘤和骨肉瘤的特定治疗靶点。

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.