Project 3: Defining the biologic role and therapeutic implications of lncRNA in multiple myeloma

项目概要-项目3丹娜-法伯癌症研究所 我们长期以来的重点是了解多发性骨髓瘤（MM）-骨髓基质细胞 互动我们已经利用了整合的基因组和表观基因组分析以及我们的体外和体内模型， 骨髓（BM）环境中的MM细胞，以鉴定支持骨髓瘤细胞的分子靶点和途径 生长，生存和耐药性，并实施有效的基于分子的治疗，效果显著 MM患者的生存率。在目前的资助期间，我们确定并验证了 控制基因转录和驱动疾病的基因调控网络和前馈环 行为，然后评估目标代理人。在这个过程中，我们发现了非编码RNA， （lncRNA）网络在MM。研究的新兴领域之一是最近的进展 突出了lncRNA的功能意义），其跨越了人类基因组的80%。这些RNA 分子通过机制控制各种细胞和分子功能， 介绍了我们先前已经描述了MM中的异常lncRNA景观，并报道了显著的 异常lncRNA作为临床结果的独立风险预测因子的作用，为以下研究提供了依据： 我们进一步研究了MM中lncRNA的生物学和分子活性。 lncRNA通过其控制多个基因的能力显著影响MM的病理生物学， 作为治疗靶点。在这个项目中，我们强大的人类MM模型系统将被用来严格地 验证被鉴定为具有生物学/预后意义的新型lncRNA（Sp. Aim 1）的作用; 针对这些临床和生物学相关的新型lncRNA的单一和联合疗法 (Sp.目标2）。利用我们的基因组和转录组数据，拟议的研究将定义功能性 MM中lncRNA的分布及其对疾病病理学的影响， 用于治疗MM患者的新型转化疗法。

Project Summary – Project 3 Dana-Farber Cancer Institute Our longstanding focus has been to understand the multiple myeloma (MM)-bone marrow stromal cell interaction. We have utilized integrated genomic and epigenomic analysis and our in vitro and in vivo models of MM cell in the bone marrow (BM) milieu to identify molecular targets and pathways supporting myeloma cell growth, survival, and drug resistance, and implement effective molecularly-based therapies with dramatic effects on the survival of MM patients. During the current funding period, we identified and validated gene regulatory networks and feed-forward loops controlling gene transcription and driving disease behavior and then evaluated targeted agents. In the process we identified the noncoding RNA (lncRNA) networks in MM. One of the emerging areas of research has been the recent advances highlighting the functional significance of lncRNAs) that span > 80% of the human genome. These RNA molecules control a variety of cellular and molecular functions via mechanisms that are yet not well described. We have previously described the aberrant lncRNA landscape in MM and reported the significant role of aberrant lncRNAs as an independent risk predictor for clinical outcome, providing the rationale to further investigate biological and molecular activity of lncRNAs in MM. We hypothesize that dysregulated lncRNAs significantly impact the pathobiology of MM by their ability to control multiple genes, with the potential to serve as therapeutic targets. In this project, our robust human MM model systems will be used to stringently validate the role of novel lncRNAs (Sp. Aim 1) identified to be of biologic/prognostic significance; and develop single and combination therapies directed against these clinically and biologically relevant novel lncRNAs (Sp. Aim 2). Leveraging our genomic and transcriptomic data, the proposed studies will define the functional landscape of lncRNAs in MM and their impact on the disease pathobiology, with the potential of developing novel translational therapies for the treatment of MM patients.