Collaborating Mutations in Medulloblastoma

摘要-项目3 髓母细胞瘤（MB）是一种发生在儿童后脑的肿瘤，发病率高峰期在20 - 30岁之间。 3岁和7岁，虽然它很少发生在成年人身上。基于不断积累的分子证据， 髓母细胞瘤现在被分为四个主要的亚组。两个亚组的特征在于组成 激活发育途径，音速刺猬（SHH）和无翅（WNT）。第3组（G3），其中 C-MYC（MYC）过度表达，而第4组（G4）的特征不太清楚，携带的情况更差 预后在上一个融资周期，我们与P01的同事合作， 模拟人G3 MB的组织学和分子特征的模型。这种小鼠模型允许 通过高通量筛选鉴定了两种FDA批准的药物， 小鼠或人G3 MB，当单独使用或组合使用时。 最近对MB的全基因组测序表明，修饰组蛋白H3的酶中的突变是 是MB最常见的异常之一。在G3 MB中，组蛋白H3赖氨酸的功能缺失突变 27（H3 K27）去甲基化酶KDM 6A或H3 K27甲基化酶的相互排斥的过表达模式 EZH 2驱动组蛋白H3赖氨酸27三甲基化水平升高。我们会用我们的老鼠模型和病人- 衍生的G3髓母细胞瘤异种移植物以研究组蛋白H3修饰在G3 MB中的作用， 包括具体评估EZH 2和KDM 6A对G3 MB开发的贡献， G3 MB的表观遗传特征。我们将筛选具有良好注释和验证的化合物库， 表观遗传修饰，将在小鼠和人G3荷瘤动物中作为单药进行评估，或 与目前的治疗方案相结合。 这些研究将为MYC、表观遗传学、神经系统发育和遗传学之间的联系提供新的见解。 发育和MB肿瘤发生。

Summary – Project 3 Medulloblastoma (MB) is a tumor of the hindbrain that occurs in children with a peak incidence between the ages of 3 and 7, although it can occur rarely in adults. Based on accumulating molecular evidence, medulloblastoma is now classified into four major subgroups. Two subgroups are characterized by constitutive activation of developmental pathways, Sonic Hedgehog (SHH) and Wingless (WNT). Group 3 (G3), in which C-MYC (MYC) is over-expressed, and Group 4 (G4), are less well characterized and carry the worse prognosis. During the last funding cycle, in collaboration with our P01 colleagues, we developed a mouse model that mimicked the histological and molecular features of human G3 MB. This mouse model allowed the identification of two FDA-approved drugs by high-throughput screening, that increased survival of mice bearing either mouse of human G3 MBs, when used alone or in combination. Recent genome-wide sequencing of MBs showed that mutations in enzymes that modify histone H3 are among the most common abnormalities in MB. In G3 MB, loss of function mutations of the histone H3 lysine 27 (H3K27) de-methylase KDM6A or mutually exclusive patterns of overexpression of the H3K27 methylase EZH2 drive elevated levels of histone H3 lysine 27 trimethylation. We will use our mouse model and patient- derived xenografts of G3 medulloblastoma to investigate the role of histone H3 modification in G3 MB, including specific evaluation of the contribution of EZH2 and KDM6A to G3 MB development and the epigenetic signature of G3 MBs. We will screen libraries of well-annotated and validated compounds targeting epigenetic modifers that will be assessed in mouse and human G3 tumor-bearing animals as single agents or in combination with current therapeutic regimens. These studies will provide new insights into the connections between MYC, epigenetics, neural development and MB tumorigenesis.