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: 10739555
• 负责人: Michael D. Taylor
• 金额: $ 64.39万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 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 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10739555
• 关键词: Dysregulation; Core; Binding; Factor; Complex

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.

项目总结 髓母细胞瘤是儿童最常见的恶性脑肿瘤。尽管积极的治疗方法 预后有所改善，许多MB患者仍然死于他们的疾病，幸存者遭受严重的长期副作用 治疗的效果。MB包括四个子组-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有所不同。我们对此有一定的了解 WNT、SHH和第3组肿瘤的分子机制，但驱动第4组的途径 髓母细胞瘤(G4MB)是这种疾病最常见的形式，仍然是一个谜。在……方面缺乏进展 G4MB是由于对导致这种疾病的基因、细胞和过程缺乏了解所致。最近， 我们确定了G4MB的一个假定起源细胞和一个多蛋白复合体，其成员在 大多数G4肿瘤。我们的初步研究表明，G4MB起源于一个双潜能群体 产生谷氨酸能神经元的菱形唇部的前体细胞，包括单极刷状细胞(UBC) 颗粒神经元(GNS)。这些祖细胞的命运由核心结合因子(CBFA)控制 复合体，包含转录共抑制物、转录因子、组蛋白去甲基酶和组蛋白 甲基转移酶。在早期发育过程中，这个复合体维持细胞处于祖细胞状态。稍后，当 该复合体失活，细胞分化为GNS和UBC。防止停用的更改 据预测，这种复合体的一部分可以阻止分化，并保持细胞处于祖细胞状态。重要的是，我们 发现这种复合体成员的基因改变是G4MB中最常见的驱动事件之一。 我们假设CBFA复合体中的突变破坏了正常的分化，并构成了核心 G4MB的突变途径，靶向该复合体将改善G4MB患者的预后。为了测试这一点 假设，我们将确定CBFA复合体是如何调节分化和肿瘤发生的，测试 该复合体的改变可以驱动G4MB肿瘤的发生，并决定是否靶向CBFA复合体 促进分化，抑制G4MB。总的来说，这些研究将解决基本问题。 关于G4MB肿瘤发生的起源和潜在机制，以及新发现的探索 为这一毁灭性疾病的治疗开发新的方法。