Mutations and target genes in Adenoid Cystic Carcinoma

描述(申请人提供)：囊性癌(ACC)是唾液腺肿瘤中最常见的一种，长期预后较差。ACC的治疗包括复杂的头颈部手术和局部放射治疗，这可能会治愈局部疾病，但会使患者毁容，并具有显著的发病率。此外，大多数患者最终死于远处转移，因此为ACC患者找到改进的治疗策略是必要的。ACC肿瘤的特点是反复易位t(6：9)，将染色体6q上的MYB(c-Myb)原癌基因与9p上的NFIB基因融合，导致新的Myb-NFIB融合癌蛋白的表达。C-Myb蛋白编码一种潜在的致癌转录因子，调节造血细胞、上皮细胞和神经细胞的分化和增殖，Myb-NFIB融合蛋白具有完整的N端Myb DNA结合域，但与NFIB融合的C端结构域发生变化。本实验室以前的研究表明，c-Myb的C-末端结构域控制其靶基因的选择，因此Myb-NFIB融合蛋白可能调控不同于正常c-Myb的基因集。我们提出了三个特定的目标来识别ACC肿瘤中的Myb-NFIB靶基因，并确定它们如何以及为什么被Myb-NFIB融合癌蛋白靶向。我们组建了一支拥有Myb蛋白质生物学、基因组学、下一代测序技术、生物统计学、生物信息学和计算方法专业知识的研究团队，以确保该项目的成功。我们提议的实验将提供关于ACC肿瘤原因的基本信息，它们将产生重要的表观遗传学和基因表达数据集，这些数据集将是高度信息量的，并将有助于指导这种毁灭性疾病的新治疗策略的开发。

DESCRIPTION (provided by applicant): Cystic Carcinoma (ACC) is one of the most common forms of salivary gland tumors and has a poor long-term prognosis. Therapy for ACC involves complicated head and neck surgery followed by local radiation treatments, which may cure the local disease but leaves patients disfigured and with significant morbidity. In addition, most patients eventually succumb from distant metastases, so finding improved treatment strategies for ACC patients is a necessity. ACC tumors are frequently characterized by a recurrent translocation t(6:9), which fuses the MYB (c-Myb) proto-oncogene on chromosome 6q to the NFIB gene on chromosome 9p, resulting in the expression of novel Myb-NFIB fusion oncoproteins. The c-Myb protein encodes a potentially oncogenic transcription factor that regulates differentiation and proliferation in hematopoietic, epithelial and neural cells, and the Myb-NFIB fusion proteins have intact N-terminal Myb DNA binding domains but altered C-terminal domains fused to NFIB. Previous studies in our laboratory showed that the C-terminal domains of c-Myb control its selection of target genes, so the Myb-NFIB fusion proteins are likely to regulate different sets of genes than normal c-Myb. We propose three specific aims to identify the Myb-NFIB target genes in ACC tumors and to determine how and why they are targeted by the Myb-NFIB fusion oncoprotein. We have assembled a team of investigators with expertise in Myb protein biology, genomics, next-generation sequencing technologies, biostatistics, bioinformatics and computational methods to insure the success of this project. The experiments we propose will provide fundamental information about the causes of ACC tumors and they will produce important epigenetic and gene expression data sets that will be highly informative and that will help guide the development of novel therapeutic strategies for this devastating disease.