Mutations and target genes in Adenoid Cystic Carcinoma

腺样囊性癌的突变和靶基因

基本信息

批准号：
8444125
负责人：
SCOTT A. NESS
金额：
$ 45.01万
依托单位：
UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-10 至 2016-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8444125
关键词：
Address Adenoid Cystic Carcinoma Alternative Splicing Bioinformatics Biological Assay Biology Biometry Breast C-terminal Carcinoma Chimeric Proteins Chromosomal translocation Chromosomes Computing Methodologies DNA Binding Domain Data Set Development Disease Distant Distant Metastasis Epigenetic Process Epithelial Epithelial Cells Gene Expression Gene Targeting Genes Genomics Goals Head and Neck Surgery Hematopoietic Laboratories Lead Life Link MYB gene Major salivary gland structure Malignant Neoplasms Maps Methods Minor Molecular Morbidity - disease rate Mutate Mutation N-terminal NFIB gene Neurons Normal Cell Oncogene Proteins Oncogenic Pathway interactions Patients Play Point Mutation Proteins Proto-Oncogene Proteins c-myb Radiation Reagent Recurrence Regulation Regulator Genes Regulatory Pathway Research Personnel Role Salivary Gland Neoplasms Salivary Glands Signal Pathway Signaling Molecule Specificity Structure Technology Tumor Suppressor Genes Variant Work combinatorial functional group genetic regulatory protein human NFIB protein improved innovation insight leukemia neoplastic cell next generation novel novel therapeutics outcome forecast promoter research study success transcription factor treatment strategy tumor

项目摘要

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. PUBLIC HEALTH RELEVANCE: This project focuses on the activities of a mutated regulator of gene expression, Myb-NFIB that is often produced as a result of a chromosomal translocation in Adenoid Cystic Carcinomas, one of the most common and most devastating forms of salivary gland tumors. We will investigate the functions of the aberrant regulatory protein produced in these tumors to determine how it contributes to tumor formation and to plot new strategies for disrupting its functions as treatments for this disease.

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治疗涉及复杂的头颈手术，然后进行局部放射治疗，这可能治愈局部疾病，但会使患者毁容并具有明显的发病率。此外，大多数患者最终会从远处转移中屈服，因此为ACC患者找到改进的治疗策略是必要的。 ACC肿瘤经常以复发性易位t（6：9）为特征，该易位t（6：9）在6q染色体上融合了Myb（C-MYB）原型癌基因，在9p染色体上融合了NFIB基因，从而表达了新型Myb-Nfib融合融合蛋白的表达。 C-MYB蛋白编码一种潜在的致癌转录因子，该因子调节造血，上皮和神经细胞的分化和增殖，MYB-NFIB融合蛋白具有完整的N末端MYB DNA DNA结合结构域，但C-末端却改变了C端域融合了NFIB。我们实验室中的先前研究表明，C-MYB的C末端结构域控制其靶基因的选择，因此MYB-NFIB融合蛋白可能比正常C-MYB调节不同的基因集。我们提出了三个特定的目的，以鉴定ACC肿瘤中的MYB-NFIB靶基因，并确定MYB-NFIB融合肿瘤蛋白的靶向以及为什么靶向。我们已经组建了一个研究人员团队，具有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的专业知识，以确保该项目的成功。我们提出的实验将提供有关ACC肿瘤原因的基本信息，它们将产生重要的表观遗传和基因表达数据集，这些数据集将非常有用，这将有助于指导这种毁灭性疾病的新型治疗策略的发展。公共卫生相关性：该项目着重于基因表达的突变调节剂MYB-NFIB的活性，该活动通常是由于腺样性囊性癌中染色体易位而产生的，腺体囊性癌是唾液腺肿瘤的最常见和最毁灭性形式之一。我们将研究这些肿瘤中产生的异常调节蛋白的功能，以确定其如何促进肿瘤形成，并绘制破坏其作为该疾病治疗的功能的新策略。