Pathogenesis of NUT-Rearranged Carcinoma

描述（由申请人提供）：t(15;19)（p13.1;q13）定义了一种罕见的、均匀致死的、未分化的年轻人中线癌，其产物是BRD4-NUT1融合癌基因。BRD4-NUT1癌（bnc）的分子机制与癌症不同，但与白血病和肉瘤相似。白血病融合癌基因的研究为肿瘤发生途径和正常的造血发育提供了重要的见解。这些见解导致了合理分子疗法的发展。预测的BRD4-NUT1融合蛋白包含两个brd4衍生的溴结构域，它们与转录活性染色质区域的乙酰化组蛋白结合，以及两个nut1衍生的转录激活结构域。我们发现BRD4-NUT1从BNC细胞系中退出后，在体外和体内产生了与诱导鳞状分化一致的显著变化，这表明BRD4-NUT1通过阻断终末上皮分化参与了癌变。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申请中提出的研究：BRD4-NUT1通过改变上皮细胞分化的关键调控因子的转录来阻断分化。2. 这种转录的改变是由NUT1与特定蛋白质伴侣的相互作用引起的。潜在的潜台词是，这些研究可能阐明对上皮细胞分化、增殖和肿瘤形成至关重要的途径。在此过程中，希望能够出现与bnc和其他可能的上皮肿瘤相关的新的合理治疗策略。基于这些初步数据和假设，我们提出以下三个具体目标：

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.