TARGETING EPIGENOMIC SIGNATURES IN NON-HODGKIN LYMPHOMA FOR NOVEL THERAPEUTICS

描述(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2万例。DLBCL是一种侵袭性肿瘤，尽管对初始治疗有很高的应答率，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对DLBCL的治疗大有裨益。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染色质的DNA和组蛋白成分上的共价标记组成，它们形成了调节基因表达的不同模式。正常表观遗传模式的改变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比，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，但包括DLBCL在内的绝大多数人类疾病的表观遗传学变化及其潜在机制仍不清楚。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，这些特征可以作为疾病的报告者，并为促进淋巴肿大的基因调控机制提供见解。这些信号的一个子集可能对应于协调DLBCL肿瘤中基因队列异常表达的新控制元件(基因间肿瘤特异性控制中心；ITCHs)。我们现在提出一个变革性的研究计划，依赖于基础和临床科学家之间的既定合作，以(I)将原发DLBCL肿瘤的表观基因组与来自每个患者的匹配的循环B细胞进行比较，(Ii)识别控制某些DLBCL基因队列的不适当表达的ITCH，以及(Iii)创新一种称为控制中心的聚焦表观遗传疗法(FETCH)的治疗方法，其中ITCH专门针对逆转其异常的表观遗传格局，从而恢复其基因队列的正常表达。总之，这些研究不仅将为评估表观基因组学方法治疗非霍奇金淋巴瘤和其他癌症的可行性提供基础数据集，而且还将指导未来开发精确的表观遗传学疗法，以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.