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，发病率最高的是 3岁和7岁，尽管这种情况在成年人中很少发生。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亚型。两个子群的特征是构成的 激活发育途径，Sonic Hedgehog(SHH)和Wingless(WNT)。第3组(G3)，其中 C-MYC(MYC)过度表达，第4组(G4)特征较差，携带较差 预后。在上一个资金周期中，我们与P01的同事合作，开发了一款鼠标 模拟人类G3MB的组织学和分子特征的模型。此鼠标模型允许 通过高通量筛选鉴定FDA批准的两种药物，提高荷瘤小鼠的存活率 单独使用或组合使用时，人类G3 MBS的任一种。 最近对MBS的全基因组测序显示，修饰组蛋白H3的酶的突变是 甲基溴中最常见的异常之一。在G3MB中，组蛋白H3赖氨酸的功能突变丢失 27(H3K27)去甲基酶KDM6A或H3K27甲基酶过度表达的互斥模式 EZH2驱动组蛋白H3赖氨酸27三甲基化水平升高。我们将使用我们的小鼠模型和患者- G3髓母细胞瘤来源的异种移植瘤研究组蛋白H3修饰对G3MB的作用 包括具体评估EZH2和KDM6A对G3 MB发展的贡献以及 G3MBS的表观遗传学特征。我们将筛选经过良好注释和验证的靶向化合物文库 表观遗传修饰剂将在小鼠和人类G3荷瘤动物中作为单一药物或 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 发育和MB肿瘤的发生。

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.