Pathogenesis of NUT-Rearranged Carcinoma

描述（由申请人提供）：一种罕见的、均匀致死的、未分化的年轻人中线癌，由t（15;19）（p13.1;q13）定义，其产物是BRD 4-NUT 1融合癌基因。BRD 4-NUT 1癌（BNC）的分子机制对于癌来说是不寻常的，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见解。这些见解导致了合理的分子疗法的发展。预测的BRD 4-NUT 1融合蛋白含有两个BRD 4衍生的溴结构域，其结合转录活性染色质区域中的乙酰化组蛋白，和两个NUT 1衍生的转录激活结构域。我们已经发现，从BNC细胞系中撤出BRD 4-NUT 1导致体外和体内的显著变化，这与鳞状分化的诱导一致，表明BRD 4-NUT 1通过阻断终末上皮分化而促进癌发生。这些观察使我们提出了两个假设，用于组织本申请中提出的研究：1。BRD 4-NUT 1通过改变上皮细胞分化的关键调节因子的转录来阻断分化。2.这种转录的改变是通过NUT 1与特定蛋白质伴侣的相互作用来实现的。一个潜在的潜台词是，这些研究可能阐明的途径是至关重要的上皮细胞分化，增殖和肿瘤。在这样做的过程中，希望与BNC和可能的其他上皮肿瘤相关的新的合理治疗策略将出现。根据这些初步数据和假设，我们提出以下三个具体目标： 1.鉴定BRD 4-NUT 1的结构域，这些结构域是阻断分化所必需的且足以阻断分化。 2.鉴定BRD 4-NUT 1相互作用蛋白，其执行导致分化阻断的下游事件。 3.鉴定BRD 4-NUT 1的转录靶点，其负责阻断BRD 4-NUT 1癌细胞的分化。

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.