T(15;19) in Aggressive Pediatric Carcinoma

描述（由申请人提供）：候选人是病理学家， 在过去的一年里，全职进行研究，并获得了大量的 具有分子细胞遗传学和基因作图方法的经验。通过这个 工作，他已经确定了一个融合癌基因的染色体靶向 易位，t（15;19），在一个非常积极的形式的癌。 这个应用程序概述了一个计划，提供了广泛的接触癌症生物学 研究方法和阐明致癌机制相关的 t（15;19）。目的是：（1）学习技能，概念和理论 癌蛋白的分子遗传学和功能分析方法; (2)鉴定（15;19）相关融合癌蛋白，并揭示其功能 这种蛋白质的特性。首要目标是确定候选人 作为一个独立资助的医生，科学家谁可以贡献原创 癌症生物学和临床医学的发现和概念。的 环境非常适合这个目标。导师？实验室有 在分子遗传学和功能分析方面的大量专业知识， 致癌基因此外，候选人？的咨询委员会有广泛的 使用体外和小鼠模型的癌症生物学经验。导师和 该委员会将促进科学互动， 合作，并将确保密集的课程，包括实验室 工作和教学课程，无论是在哈佛医学院内外 地区，以满足在癌症生物学的广泛经验的目的。 研究部分的重点是一种毁灭性的癌症形式， 易位t（15;19）（q13;p13.1）。这种独特的癌症已经完全 对多药化疗和放疗无反应， 患者（儿童和年轻人）在9个月内死亡 诊断.候选人通过以下方式定位易位断点： 细胞遗传学，荧光原位杂交（FISH），Southern印迹，和 RT-PCR方法。他的初步研究最近发现了 癌基因，由编码细胞的19号染色体伴侣癌基因组成 增殖相关布罗莫结构域蛋白，与15号染色体融合 编码一种新的富含脯氨酸的蛋白质的伴癌基因。未来的研究将 聚焦三个目标。首先，全长t（15;19）融合癌基因将被 其特征在于cDNA末端的快速扩增，并且如果需要， 从t（15;19）癌细胞系筛选cDNA文库。第二，他将 建立评价t（15;19）癌蛋白的体外模型 转化活性和转化机制。这些研究将解决 假设t（15;19）癌蛋白的作用是通过去调节 一种或两种天然蛋白质。第三，他将决定 使用FISH和RT-PCR检测，在临床侵袭性肿瘤中t（15;19）的频率 儿科患者的癌症。这些研究还将揭示 T（15;19）+癌发生的原发部位。

DESCRIPTION (provided by applicant): The candidate is a pathologist who has performed research full-time over the past year and has acquired substantial experience in molecular cytogenetic and gene mapping methods. Through this work, he has identified a fusion oncogene targeted by a chromosomal translocation, t(15;19), in an extraordinarily aggressive form of carcinoma. This application outlines a plan to provide a broad exposure to cancer biology research methods and to elucidate the oncogenic mechanisms associated with t(15;19). The aims are to: (1) learn skills, conceptual and theoretical approaches to molecular genetics and functional analysis of oncoproteins; and (2) identify the (15;19)-associated fusion oncoprotein and reveal functional properties of this protein. The overriding aim is to establish the candidate as an independently funded physician-scientist who can contribute original findings and concepts to cancer biology and clinical medicine. The environment is well suited to this goal. The mentor?s laboratory has substantial expertise in molecular genetics and the functional analysis of oncogenes. In addition, the candidate?s advisory committee has broad experience in cancer biology using in vitro and murine models. The mentor and t h e a dvisory committee will facilitate scientific interactions and collaborations, and will ensure an intensive curriculum, including laboratory work and didactic courses, both within and outside of the Harvard Medical Area, in order to meet the aim of a broad experience in cancer biology. The research component focuses on a devastating form of carcinoma with translocation t(15;19)(q13;p13.1). This unique carcinoma has been completely unresponsive to multi-agent chemotherapy and radiation therapy, and all patients (children and young adults) have succumbed within 9 months of diagnosis. The candidate has localized the translocation breakpoints by cytogenetic, fluorescence in situ hybridization (FISH), Southern blotting, and RT-PCR methods. His preliminary studies have recently identified the fusion oncogene, comprised of a chromosome 19 partner oncogene encoding a cell proliferation-related bromodomain protein, fused with the chromosome 15 partner oncogene encoding a novel proline-rich protein. Future studies will focus on three aims. First, the full length t(15;19) fusion oncogene will be characterized by rapid amplification of cDNA ends and, if necessary, by screening cDNA libraries from a t(15;19) cancer cell line. Second, he will establish in vitro models with which to evaluate the t(15;19) oncoprotein transforming activity and transforming mechanisms. These studies will address the hypothesis that the t(15;19) oncoprotein acts by deregulating function of one or both of its component native proteins. Third, he will determine the frequency of t(15;19), using FISH and RT-PCR assays, in clinically aggressive carcinomas from pediatric patients. These studies will also reveal the range of primary sites from which t(15;19)+ carcinomas arise.