TARGETING EPIGENOMIC SIGNATURES IN NON-HODGKIN LYMPHOMA FOR NOVEL THERAPEUTICS

针对非霍奇金淋巴瘤的表观基因组特征进行新型治疗

• 批准号: 8151066
• 负责人: Eugene M Oltz
• 金额: $ 63.89万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-29 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8151066
• 关键词: Accounting; B-Lymphocytes; Cell Nucleus; Chromatin; Clinical; Collaborations; DNA; DNA Packaging; Data Set; Diagnosis; Diagnostic; Disease; Elements; Epigenetic Process; Future; Gene Activation; Gene Expression; Gene Expression Regulation; Gene Silencing; Genes; Genetic; Genome; Goals; Heart; Histones; Lead; Lesion; Link; Lymphocyte; Lymphoma; Lymphomagenesis; Malignant Neoplasms; Modality; Modification; Non-Hodgkin' s Lymphoma; Pathology; Patients; Pattern; Reporter; Research; Scientist; Therapeutic; Tumor Suppressor Genes; United States; cancer cell; chromatin modification; cohort; epigenomics; gene function; human disease; innovation; insight; large cell Diffuse non-Hodgkin' s lymphoma; novel; novel therapeutics; programs; promoter; public health relevance; response; restoration; tumor

DESCRIPTION (provided by applicant): Diffuse large B cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin lymphoma (NHL) diagnosed in the United States, accounting for over 20,000 new cases annually. DLBCL is an aggressive tumor and, despite a high response rate to initial therapy, approximately 40% of patients will ultimately die from their lymphoma. Treatment of DLBCL would benefit greatly from the advent of early diagnostics and new therapeutics. The emerging field of epigenomics is expected to provide such opportunities for most diseases, including DLBCL. The epigenome consists of covalent marks placed on the DNA and histone components of chromatin, which form distinct patterns to regulate gene expression. Changes in normal epigenetic patterns lead to inappropriate gene activation or silencing, which has been linked to numerous pathologies. For example, cancer cells silence tumor suppressor genes by revising the pattern of chromatin modifications near transcriptional promoters. In contrast to the immutability of disease-causing genetic lesions, epigenetic modifications are reversible, offering the possibility of new therapeutic modalities. Despite recent progress, the vast majority of epigenetic changes that characterize human disease, including DLBCL, and their underlying mechanisms remain unknown. We hypothesize that that the epigenome of DLBCL tumors from different patients will harbor common signatures that can be used as reporters for the disease and provide insights into mechanisms of gene regulation that promote lymphomagenesis. A subset of these signatures likely corresponds to new control elements that coordinate the aberrant expression of gene cohorts in DLBCL tumors (Intergenic Tumor-specific Control Hubs; ITCHs). We now propose a transformational research plan relying on established collaborations between basic and clinical scientists to (i) compare the epigenomes of primary DLBCL tumors with matched circulating B cells from each patient, (ii) identify ITCHs that govern the inappropriate expression of certain DLBCL gene cohorts, and (iii) innovate a therapeutic approach called Focused Epigenetic Therapy of Control Hubs (FETCH), in which ITCHs are specifically targeted for reversal of their abnormal epigenetic landscape with consequential restoration of normal expression at their gene cohorts. Together, these studies will not only provide a foundational dataset for gauging the feasibility of epigenomic approaches to NHL and other cancers, but will also guide future efforts to develop precision epigenetic therapies for reversing aberrant gene expression patterns that characterize a wide range of human diseases. PUBLIC HEALTH RELEVANCE: The packaging of DNA in the nucleus is a key determinant of gene function; changes in these "epigenetic" programs are likely to be at the heart of many diseases. We propose studies to characterize the epigenome of lymphocytes in patients suffering from a common form of non-Hodgkin Lymphoma, with the goal of establishing tumor-specific epigenetic signatures. The signatures will then be targeted for a novel therapy in which abnormal epigenetic patterns are reversed specifically at regions in the genome that control the inappropriate expression of lymphoma genes.

描述（由申请人提供）：弥漫性大 B 细胞淋巴瘤 (DLBCL) 是美国诊断的最常见的非霍奇金淋巴瘤 (NHL) 亚型，每年新增病例超过 20,000 例。 DLBCL 是一种侵袭性肿瘤，尽管对初始治疗的反应率很高，但大约 40% 的患者最终将死于淋巴瘤。 DLBCL 的治疗将大大受益于早期诊断和新疗法的出现。新兴的表观基因组学领域有望为包括 DLBCL 在内的大多数疾病提供这样的机会。表观基因组由位于染色质 DNA 和组蛋白成分上的共价标记组成，这些标记形成独特的模式来调节基因表达。正常表观遗传模式的变化会导致不适当的基因激活或沉默，这与许多病理学有关。例如，癌细胞通过修改转录启动子附近的染色质修饰模式来沉默肿瘤抑制基因。与致病基因损伤的不变性相反，表观遗传修饰是可逆的，为新的治疗方式提供了可能性。尽管最近取得了进展，但人类疾病（包括 DLBCL）的绝大多数表观遗传变化及其潜在机制仍然未知。我们假设来自不同患者的 DLBCL 肿瘤的表观基因组将具有共同的特征，可以用作该疾病的报告基因，并为促进淋巴瘤发生的基因调控机制提供见解。这些特征的一个子集可能对应于协调 DLBCL 肿瘤中基因组异常表达的新控制元件（基因间肿瘤特异性控制中心；ITCH）。我们现在提出了一项依赖于基础科学家和临床科学家之间已建立的合作的转化研究计划，以（i）将原发性 DLBCL 肿瘤的表观基因组与每位患者的匹配循环 B 细胞进行比较，（ii）识别控制某些 DLBCL 基因组的不当表达的 ITCH，以及（iii）创新一种称为控制中枢聚焦表观遗传疗法（FETCH）的治疗方法，其中 ITCH 专门用于逆转其异常表观遗传景观，从而恢复其基因组的正常表达。总之，这些研究不仅将为衡量非霍奇金淋巴瘤和其他癌症的表观基因组方法的可行性提供基础数据集，还将指导未来开发精准表观遗传疗法的努力，以逆转表征多种人类疾病的异常基因表达模式。 公共卫生相关性：细胞核中 DNA 的包装是基因功能的关键决定因素；这些“表观遗传”程序的变化可能是许多疾病的核心。我们提出研究来表征患有常见形式的非霍奇金淋巴瘤的患者淋巴细胞的表观基因组，目的是建立肿瘤特异性表观遗传特征。然后，这些特征将被用于一种新的疗法，在这种疗法中，异常的表观遗传模式会在基因组中控制淋巴瘤基因不适当表达的区域被特别逆转。