Collaborating Mutations in Medulloblastoma

髓母细胞瘤中的协同突变

• 批准号: 7647495
• 负责人: MARTINE F. ROUSSEL (SHERR)
• 金额: $ 30.96万
• 依托单位: ST. JUDE CHILDREN'S RESEARCH HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-04-01 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7647495
• 关键词: Affect; Anaplastic Cell; Brain; Cell Cycle; Cerebellum; Child; Cyclin D1; Defect; Development; Disease; Down-Regulation; Engineering; Erinaceidae; Fostering; Frequencies; Gene Dosage; Gene Expression; Gene Mutation; Genes; Genetic; Human; Lead; Maintenance; Malignant Neoplasms; Malignant neoplasm of brain; Methods; MicroRNAs; Mitogens; Molecular; Molecular Profiling; Mouse Strains; Mus; Mutation; Neoplasms; Neurocognitive; Neuronal Differentiation; Oncogene Proteins; Operative Surgical Procedures; Other Genetics; Patients; Pediatric Neoplasm; Protein p53; Proteins; RNA; Radiation therapy; Resistance; Role; Signal Pathway; Signal Transduction; Stem cells; TP53 gene; Tumor Suppressor Proteins; Work; bone morphogenic protein; chemotherapy; improved; kinase inhibitor; loss of function; medulloblastoma; mouse model; novel; transcription factor; tumor

Medulloblastoma (MB) is the most common malignant brain tumor in children. MB is thought to arise from progenitor cells in the developing cerebellum that fail to exit the cell division cycle properly, thus providing fertile ground for tumor formation. Many genetic anomalies have been identified in human MB, but only a few have been revealed to be causative. We have genetically engineered two different MB-prone mouse strains that lack the cyclin-D-dependent kinase inhibitor, p18lnk4c, a cell cycle regulatory and tumor suppressor protein whose expression was also revealed to be reduced or absent in human MBs. In Specific Aim 1, we propose to document the frequency of inactivation of INK4C/CDKN2C in human MBs and to correlate its loss-of-function with other genetic mutations, gene copy number alterations, and gene expression profiles that define different human MB subsets. We will also explore the combined roles of the C-MYC oncoprotein and p53 tumor suppressor in generating a mouse model of large cell anaplastic MBs, the most aggressive and treatment-resistant form of the disease. Many mouse MBs are characterized by mutations affecting a signaling pathway dominated by the mitogen, Sonic Hedgehog (Shh); genetic alterations affecting the Shh signaling pathway have similarly been documented in a subset of human MBs. Our work has established a role for the bone morphogenic proteins (BMPs) in countering Shh signaling, thereby inhibiting proliferation of mouse MBs, and fostering their neuronal differentiation. Not only do BMPs strongly antagonize MB formation in our mouse models, but downregulation of many BMP-responsive genes is a hallmark of Shh-driven human tumors. In Specific Aim 2, we will study Mathl, a key transcription factor regulated by BMP signaling in an'effort to discern how the activity of this protein is governed, what genes it regulates, and why its role is seemingly essential for MB development. Finally, it is now widely appreciated that small regulatory RNA species (micro-RNAs) globally regulate gene expression and thereby contribute to many forms of cancer. In Specific Aim 3, we propose methods to characterize in detail the micro-RNAs that contribute to MB formation and tumor maintenance in both mice and humans.

髓母细胞瘤是儿童最常见的恶性脑肿瘤。甲基溴被认为是由 发育中的小脑中未能正常退出细胞分裂周期的前体细胞，从而提供 形成肿瘤的肥沃土壤。在人类MB中发现了许多遗传异常，但只有一种 几乎没有人被发现是致病原因。我们通过基因工程培育出了两种不同的易感染MB的小鼠 缺乏细胞周期调节蛋白p18lnk4c的细胞周期蛋白依赖的激酶抑制因子p18lnk4c的菌株 抑制蛋白，其在人的MBS中的表达也被下调或缺失。具体而言 目的1，我们建议记录INK4C/CDKN2C在人MBS中的失活频率，并 它的功能丧失与其他基因突变、基因拷贝数改变和基因 定义不同人类MB亚集的表达谱。我们还将探讨 C-myc癌蛋白和p53抑癌基因在大细胞间变性骨髓瘤小鼠模型建立中的作用 最具侵袭性和对治疗耐药的疾病形式。许多鼠标MBS的特征是 影响由有丝分裂原Sonic Hedgehog(Shh)控制的信号通路的突变；遗传 影响Shh信号通路的改变在人类MBS的一个子集中也有类似的记录。 我们的工作确定了骨形态发生蛋白(BMPs)在对抗Shh信号中的作用， 从而抑制小鼠骨髓间充质干细胞的增殖，促进其神经分化。不仅BMP 在我们的小鼠模型中强烈拮抗MB的形成，但下调了许多BMP反应基因 是Shh驱动的人类肿瘤的一个标志。在特定目标2中，我们将研究关键转录因子Mathl 由BMP信号调节，以努力辨别这种蛋白质的活性是如何调控的，它是什么基因 管理，以及为什么它的作用似乎对甲基溴的发展至关重要。最后，它现在得到了广泛的赞赏 小调节RNA物种(MicroRNA)在全球范围内调节基因表达，从而有助于 多种癌症。在具体目标3中，我们提出了详细描述微小RNA的方法 有助于小鼠和人类体内MB的形成和肿瘤的维持。