Mutations and target genes in Adenoid Cystic Carcinoma

描述（由申请人提供）：囊性癌（ACC）是唾液腺肿瘤最常见的形式之一，长期预后较差。ACC的治疗包括复杂的头颈部手术，然后进行局部放射治疗，这可以治愈局部疾病，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患者寻找改进的治疗策略是必要的。ACC肿瘤通常以复发性易位t（6:9）为特征，易位t将染色体6q上的MYB （c-Myb）原癌基因与染色体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结合结构域，但与NFIB融合的c端结构域发生了改变。我们实验室之前的研究表明，c-Myb的c端结构域控制着其对靶基因的选择，因此Myb-NFIB融合蛋白可能调控的是与正常c-Myb不同的一组基因。我们提出了三个具体目标，以鉴定ACC肿瘤中的Myb-NFIB靶基因，并确定Myb-NFIB融合癌蛋白如何以及为何靶向它们。我们在Myb蛋白生物学、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方面组建了一支专业的研究团队，以确保这个项目的成功。我们提出的实验将提供关于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，这些数据集将具有高度信息性，并将有助于指导这种毁灭性疾病的新治疗策略的发展。

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.