Pathogenesis of NUT-Rearranged Carcinoma

NUT重排癌的发病机制

• 批准号: 8071200
• 负责人: Christopher A French
• 金额: $ 29.03万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-30 至 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8071200
• 关键词: Acute leukemia; Binding; Bromodomain; Carcinoma; Cell Differentiation process; Cell Line; Child; Chimeric Proteins; Chromatin; Chromosome abnormality; Common Carcinoma; Complex; Data; Development; Dissection; Elderly; Employee Strikes; Epithelial; Epithelial Cells; Event; Genes; Genetic; Genetic Transcription; Growth; Hematopoietic; Histones; Immunophenotyping; In Vitro; Lead; Lesion; Malignant Epithelial Cell; Mediating; Molecular; Morphology; Neoplasms; Normal Cell; Nuclear Protein; Oncogene Proteins; Oncogenes; Oncogenic; Pathogenesis; Pathway interactions; Play; Proteins; Research Personnel; Role; Squamous Differentiation; Stem cells; Tertiary Protein Structure; Therapeutic; Transcription Coactivator; Transcriptional Activation Domain; Undifferentiated; Withdrawal; base; bcr-abl Fusion Proteins; carcinogenesis; cell growth; cell transformation; falls; fusion gene; in vivo; insight; leukemia; novel; programs; sarcoma; tumor; young adult

DESCRIPTION (provided by applicant): A rare, uniformly lethal, undifferentiated midline carcinoma of young people is defined by the t(15;19)(p13.1;q13), whose product is the BRD4-NUT1 fusion oncogene. The molecular mechanism of BRD4-NUT1 carcinomas (BNCs) is unusual for a carcinoma, but resembles leukemias and sarcomas. Study of leukemic fusion oncogenes has provided important insights into oncogenic pathways, and normal hematopoietic development. These insights have led to the development of rational molecular therapies. The predicted BRD4-NUT1 fusion protein contains two BRD4-derived bromodomains, which bind acetylated histones in regions of transcriptionally active chromatin, and two NUT1-derived transcriptional activation domains. We have found that withdrawal of BRD4-NUT1 from BNC cell lines results in striking changes in vitro and in vivo that are consistent with the induction of squamous differentiation, suggesting that BRD4- NUT1 contributes to carcinogenesis by blocking terminal epithelial differentiation. These observations have led us to formulate two hypotheses, which serve to organize the studies proposed in this application: 1. BRD4-NUT1 blocks differentiation by altering the transcription of critical regulator(s) of epithelial cell differentiation. 2. This alteration in transcription is enacted by the interaction of NUT1 with specific protein partners. An underlying subtext is that these studies are likely to elucidate pathways that are vital to epithelial cell differentiation, proliferation, and neoplasia. In doing so, it is hoped that new rational therapeutic strategies relevant to BNCs and possibly other epithelial tumors will emerge. Based on these preliminary data and hypotheses, we propose the following three specific aims: 1. To identify the domains of BRD4-NUT1 that are necessary and sufficient to block differentiation. 2. To identify the BRD4-NUT1-interacting proteins that execute the downstream events that lead to the blockade of differentiation. 3. To identify the transcriptional targets of BRD4-NUT1 that are responsible for the blockade of differentiation in BRD4-NUT1 carcinoma cells.

描述（由申请人提供）：T（15; 19）（P13.1; Q13）定义了一种罕见的，均匀的致命，未分化的中线癌，其产品是BRD4-NUT1融合癌基因。 BRD4-NUT1癌（BNC）的分子机制对于癌是不寻常的，但类似于白血病和肉瘤。白血病融合癌基因的研究为致癌途径和正常造血发育提供了重要的见解。这些见解导致了理性分子疗法的发展。预测的BRD4-NUT1融合蛋白包含两个BRD4衍生的溴构胺，它们结合了转录活性染色质区域中的乙酰化组蛋白，以及两个NUT1衍生的转录激活域。我们发现，从BNC细胞系中撤出BRD4-NUT1会导致体外和体内的引人注目的变化，这与鳞状分化的诱导一致，这表明BRD4-NUT1通过阻断末端上皮分化而导致致癌作用。这些观察结果使我们提出了两个假设，这些假设有助于组织本应用中提出的研究：1。BRD4-NUT1通过改变上皮细胞分化的临界调节剂的转录来阻止分化。 2。通过NUT1与特定蛋白质伴侣的相互作用来实现转录的这种改变。潜在的潜台词是这些研究可能阐明对上皮细胞分化，增殖和肿瘤至关重要的途径。这样一来，希望与BNC和可能其他上皮肿瘤有关的新的理性治疗策略会出现。基于这些初步数据和假设，我们提出以下三个具体目标： 1。确定BRD4-NUT1的域，这些域是必要且足以阻止分化的。 2。确定执行导致封锁分化的下游事件的BRD4-NUT1相互作用蛋白。 3。确定负责BRD4-NUT1癌细胞分化的封锁的BRD4-NUT1的转录靶标。