TARGETING EPIGENOMIC SIGNATURES IN NON-HODGKIN LYMPHOMA FOR NOVEL THERAPEUTICS

描述（由申请人提供）：弥漫性大B细胞淋巴瘤（DLBCL）是美国最常见的非霍奇金淋巴瘤（NHL）亚型，每年新发病例超过2万例。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。早期诊断和新疗法的出现将使DLBCL的治疗受益匪浅。表观基因组学的新兴领域有望为包括DLBCL在内的大多数疾病提供这样的机会。表观基因组由放置在DNA和染色质组蛋白组分上的共价标记组成，它们形成不同的模式来调节基因表达。正常表观遗传模式的改变导致不适当的基因激活或沉默，这与许多疾病有关。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。与致病遗传病变的不变性相反，表观遗传修饰是可逆的，提供了新的治疗方式的可能性。尽管最近取得了进展，但绝大多数人类疾病特征的表观遗传变化，包括DLBCL，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包含共同的特征，这些特征可以用作该疾病的报告者，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肿瘤基因群异常表达的新控制元件（基因间肿瘤特异性控制中心，ITCHs）。我们现在提出一个转型研究计划，依靠基础和临床科学家之间建立的合作，来(i)比较原发性DLBCL肿瘤的表观基因组与来自每个患者的匹配循环B细胞，（ii）确定控制某些DLBCL基因群不适当表达的ITCHs，以及（iii）创新一种称为集中控制中心表观遗传治疗（FETCH）的治疗方法。其中，ITCHs被专门用于逆转其异常表观遗传景观，从而恢复其基因群的正常表达。总之，这些研究不仅将提供一个基础数据集来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，而且还将指导未来开发精确的表观遗传疗法来逆转具有广泛人类疾病特征的异常基因表达模式。

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.