Dysregulation of the Core Binding Factor Complex Inhibits Differentiation and Drives Group 4 Medulloblastoma

核心结合因子复合物的失调抑制分化并驱动第 4 组髓母细胞瘤

• 批准号: 10530990
• 负责人: Michael D. Taylor
• 金额: $ 15.92万
• 依托单位: SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-04 至 2022-09-02
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10530990
• 关键词: ATAC-seq; Address; Automobile Driving; Brush Cell; Cell physiology; Cells; Characteristics; Clinic; Clinical; Complex; Core-Binding Factor; Cytoplasmic Granules; Data; Development; Disease; Engineering; Event; GFI1 gene; Genes; Genetic Transcription; Glutamates; Growth; Histones; Human; Immunocompromised Host; Impairment; In Vitro; Lead; Light; Lip structure; Lysine; Malignant neoplasm of brain; Modeling; Modification; Molecular; Monitor; Mus; Mutate; Mutation; Neuroepithelial; Neurons; Oncogenes; Outcome; Pathway interactions; Patients; Pediatric Neoplasm; Polyproteins; Population; Reporter; Role; Route; SHH gene; Subgroup; Survivors; Testing; Transplantation; aggressive therapy; base; genetic corepressor; high-throughput drug screening; histone demethylase; histone methyltransferase; improved outcome; in vivo; insight; medulloblastoma; member; new therapeutic target; novel; novel strategies; patient derived xenograft model; prevent; progenitor; side effect; single cell technology; single-cell RNA sequencing; small molecule; stem; stem cells; transcription factor; tumor; tumor growth; tumorigenesis

PROJECT SUMMARY Medulloblastoma (MB) is the most common malignant brain tumor in children. Although aggressive treatments have improved outcomes, many MB patients still die of their disease, and survivors suffer severe long-term side effects from therapy. MB comprises four subgroups—WNT, Sonic hedgehog (SHH), Group 3 and Group 4—that differ in terms of molecular alterations, clinical characteristics and outcomes. We have some understanding of the molecular mechanisms underlying WNT, SHH and Group 3 tumors, but the pathways that drive Group 4 medulloblastoma (G4MB), the most prevalent form of the disease, remain a mystery. The lack of progress on G4MB has been due to a poor understanding of the genes, cells and processes leading to the disease. Recently, we identified a putative cell of origin for G4MB and a polyprotein complex whose members are mutated in the majority of G4 tumors. Our preliminary studies suggest that G4MB arises from a population of bipotential progenitor cells in the rhombic lip that gives rise to glutamatergic neurons, including unipolar brush cells (UBCs) and granule neurons (GNs). The fate of these progenitors is controlled by the Core Binding Factor (CBFA) complex, which contains transcriptional co-repressors, transcription factors, histone demethylases and histone methyltransferases. During early development, this complex maintains cells in a progenitor state. Later, when the complex is inactivated, cells undergo differentiation into GNs and UBCs. Alterations that prevent inactivation of this complex are predicted to prevent differentiation and maintain cells in a progenitor state. Importantly, we found that genetic alterations in members of this complex are among the most common driver events in G4MB. We hypothesize that mutations in the CBFA complex derail normal differentiation and constitute the core mutational route to G4MB, and that targeting this complex will improve outcomes for G4MB patients. To test this hypothesis, we will determine how the CBFA complex regulates differentiation and tumorigenesis, test whether alteration of the complex can drive G4MB tumorigenesis, and determine whether targeting the CBFA complex promotes differentiation and inhibits G4MB. Collectively, these studies will address fundamental questions regarding the origin and underlying mechanisms driving G4MB tumorigenesis, and probe newly revealed vulnerabilities to develop novel approaches to therapy for this devastating disease.

项目摘要 髓母细胞瘤是儿童最常见的恶性脑肿瘤。虽然积极的治疗 虽然结果有所改善，但许多MB患者仍然死于疾病，幸存者遭受严重的长期副作用， 治疗的效果。MB包括四个亚组-WNT，Sonic hedgehog（SHH），第3组和第4组- 在分子改变、临床特征和结果方面不同。我们对 WNT、SHH和第3组肿瘤的分子机制，但驱动第4组肿瘤的途径 成神经管细胞瘤（G4 MB）是该疾病最普遍的形式，仍然是一个谜。缺乏进展 G4 MB是由于对导致这种疾病的基因、细胞和过程的理解不足。最近， 我们鉴定了一个假定的G4 MB起源细胞和一个多蛋白复合体，其成员在G4 MB中发生突变。 大多数G4肿瘤我们的初步研究表明，G4 MB产生于一个人口的双电位 菱形唇中的祖细胞，可产生多巴胺能神经元，包括单极刷状细胞（UBC） 和颗粒神经元（GN）。这些祖细胞的命运由核心结合因子（CBFA）控制 复合物，其包含转录辅阻遏物、转录因子、组蛋白去甲基化酶和组蛋白 甲基转移酶在早期发育过程中，这种复合物使细胞保持在祖细胞状态。后来 当复合物失活时，细胞分化为GN和UBC。防止失活的改变 预测这种复合物的存在可以阻止分化并维持细胞处于祖细胞状态。重要的是我们 发现该复合体成员的遗传改变是G4 MB中最常见的驱动事件之一。 我们假设CBFA复合物中的突变破坏了正常分化，并构成了 G4 MB的突变途径，靶向这种复合物将改善G4 MB患者的结局。为了验证这一 假设，我们将确定CBFA复合物如何调节分化和肿瘤发生，测试是否 复合物的改变可以驱动G4 MB肿瘤发生，并决定是否靶向CBFA复合物 促进分化并抑制G4 MB。总的来说，这些研究将解决基本问题， 关于G4 MB肿瘤发生的起源和潜在机制，以及新发现的探针 开发新的方法来治疗这种毁灭性的疾病。