Elucidating the epigenetic landscape of neurofibromatosis and development of therapeutic targets

项目摘要 2型神经纤维瘤病（NF 2）是一种遗传性疾病，由NF 2肿瘤的生殖系突变引起 抑制基因，并以第VIII脑神经的神经鞘瘤的发展为特征。梅林 NF 2基因的产物，在散发性神经鞘瘤，脑膜瘤， 室管膜瘤和间皮瘤。尽管过去对这种疾病的认识取得了进展， 多年来，这还没有转化为治疗方法。因此，有一个迫切和未得到满足的需要， NF 2患者的治疗选择。在分子水平上，梅林被证明是一个关键的调节器， 多种信号转导途径，包括由小G蛋白和Hippo/雅普调节的信号转导途径 通路 为了确定NF 2缺陷肿瘤的治疗弱点，我们评估了BET的活性， （Bromodomain and Extra-Terminal domain）蛋白抑制剂NF 2-null Schwann细胞。BET蛋白质是 其特征在于存在两个串联溴结构域和一个末端外结构域。溴结构域 可以特异性结合组蛋白上的乙酰化赖氨酸残基，作为表观遗传学的读者， 组蛋白乙酰化密码。我们的初步数据表明，BET抑制抑制NF 2-κ B的增殖。 在培养物和体内肿瘤生长中消除雪旺氏细胞和雪旺氏瘤细胞，这是通过 溴结构域蛋白4（BRD 4）的抑制。初步数据表明，BRD 4的作用是介导的， 在很大程度上通过调节雅普。重要的是，我们最近证明，雅普是必需的， NF 2缺陷的雪旺细胞的加速增殖和肿瘤发生。本提案的目标是 确定雪旺细胞中BET蛋白质的基本功能，并确定BET抑制是否是一种 治疗方法，应进一步发展为NF 2的治疗方式。

Project Summary Neurofibromatosis type 2 (NF2) is an inherited disorder caused by germ line mutations of the NF2 tumor suppressor gene and is characterized by development of schwannomas of the VIIIth cranial nerve. Merlin, the product of the NF2 gene, is also inactivated to a significant extent in sporadic schwannomas, meningioma, ependymoma and mesothelioma. In spite of progress made in the understanding of the disease over the past several years, this has not yet translated into therapies. Thus, there is an urgent and unmet need to develop therapeutic options for NF2 patients. At a molecular level, Merlin has been shown to function as a key regulator of multiple signal transduction pathways including those regulated by small G-proteins and the Hippo/YAP pathway. In an effort to identify therapeutic vulnerabilities in NF2-deficient tumors, we assessed the activity of the BET (Bromodomain and Extra-Terminal domain) protein inhibitors NF2-null Schwann cells. The BET proteins are characterized by the presence of two tandem bromodomains and an extra-terminal domain. The bromodomains can specifically bind acetylated lysine residues on histones, serving as epigenetic readers that decipher the histone acetylation code. Our preliminary data indicate that BET inhibition suppresses the proliferation of NF2- null Schwann and schwannoma cells in culture and tumor growth in vivo, and that this is mediated through inhibition of bromodomain protein 4 (BRD4). Preliminary data indicates that the effects of BRD4 are mediated to a significant extent via regulation of YAP. Importantly, we recently demonstrated that YAP is required for the accelerated proliferation of NF2-deficient Schwann cells and tumorigenesis. The goals of this proposal are to identify the essential functions of BET proteins in Schwann cells and determine whether BET inhibition is a therapeutic approach that should be further developed as a treatment modality for NF2.