Epigenetic Signature of Non-Hodgkin's Lymphomas

描述(由申请人提供) 非霍奇金淋巴瘤(NHL)是美国第五大最常见的恶性肿瘤，2001年估计有55000例新病例和26000例死亡。尽管过去几十年来癌症治疗的进步改善了许多血液系统恶性肿瘤患者的预后，但大多数非霍奇金淋巴瘤患者会复发并最终死于他们的疾病。挑战仍然是开发既更有效又毒性更低的靶向疗法。这项应用的总体目标是进一步开发和测试一种创新的微阵列工具，以确定CpG岛启动子和重要基因的第一外显子区域的DNA甲基化，这些基因影响转录沉默，但可能被药物去甲基化疗法逆转。这种微阵列芯片可以同时测量DNA甲基化和基因表达，因此可以提供甲基化依赖的基因沉默和逆转的直接证据。另一项创新包括开发基于符合不断发展的关于微阵列标准的国际共识的数据模型和模式的DNA甲基化实验室信息系统。这将为进一步的协作调查提供可靠和灵活的数据存储和标记为XML的信息共享选择。我们建议合并表观基因组学和计算技术，以形成评估NHL的有价值的临床实验室工具。一个跨学科的团队将应用计算研究方法来利用生物医学内容来确定特定CpG岛上与淋巴瘤相关的新的和高选择性的表观遗传学变化，这些变化可能会影响基因功能，而且可能会被药物干预逆转。新开发的微阵列和计算工具将被世界各地的其他研究人员广泛分享。对这样的调查来说，最大的智力挑战之一是提取所有可用数据的最全面的含义和影响。为期一年的R21阶段使用两类惰性NHL进行概念验证，并提供可量化的、已定义的里程碑。为期4年的R33阶段将进一步增强微阵列系统，检查其他类别的惰性NHL，并确定淋巴瘤的表观基因组特征，以改进人类NHL的分类、预后预测和潜在的治疗选择，从而改善临床结果。

DESCRIPTION (provided by applicant) Non-Hodgkin's lymphoma (NHL) is the fifth most common malignancy in the United States, accounting for an estimated 55,000 new cases and 26,000 deaths in the year 2001. Although advances in cancer treatment over the past several decades have improved outcomes for many patients with hematologic malignancies, most patients with NHL relapse and ultimately die from their disease. The challenge remains to develop targeted therapies that are both more effective and less toxic. The overall goal of this application is to further develop and test an innovative microarray tool to determine DNA methylation of CpG island promoters and 1st exon regions of important genes that affect transcriptional silencing, but may potentially be reversible by pharmacological demethylation therapies. This microarray chip can measure both DNA methylation and gene expression, and hence can provide direct evidence of methylation-dependent gene silencing and reversal. Another innovation includes development of a laboratory information system for DNA methylation based on a data model and schema compliant with an evolving international consensus on microarray standards. This will provide robust and flexible data storage and XML-tagged information sharing options for further collaborative investigations. We propose to merge epigenomic and computational technologies that can form a valuable clinical laboratory tool for assessment of NHLs. An interdisciplinary team will apply computational research methods to leverage the biomedical content to identify novel and highly selective lymphoma-related epigenetic changes in specific CpG islands that may affect gene function, and furthermore, may be potentially reversed by pharmacologic interventions. The new microarrays and computational tools developed will be widely shared among other investigators around the world. One of the greatest intellectual challenges to investigations such as this is to extract the fullest meanings and implications of all available data. The 1-year R21 phase demonstrates the proof-of-concept using 2 classes of indolent NHLs and provides quantifiable, defined milestones. The 4-year R33 phase will further enhance the microarray system, examine additional classes of indolent NHLs, and determine an Epigenomic Signature of Lymphomas to improve classification, prognostic prediction, and potentially therapeutic choices in human NHL that can improve on clinical outcomes.