Mechanisms promoting translocations and mature B cell lymphomas

描述(申请人提供)：大多数人类成熟B细胞淋巴瘤似乎起源于生发中心(GC)或生发中心后的B细胞，通常含有涉及免疫球蛋白(Ig)和癌基因的克隆性易位。GC是成熟B细胞对抗原反应形成的特殊微环境，B细胞增殖旺盛，Ig基因经历体细胞高突变(SHM)和类切换重组(CSR)两种DNA改变事件。虽然有人认为SHM或CSR过程中的DNA双链断裂(DSB)是GC来源的B细胞淋巴瘤染色体易位的主要来源，但由于缺乏适当的小鼠模型，这一点从未被直接解决。有一些很好地描述了GC来源的B细胞淋巴瘤的小鼠模型。然而，这些模型中的大多数都是基于癌基因通过淋巴细胞特异性调节区的结构性表达，这种方法无法产生克隆性易位的肿瘤。我们提出了一个新颖而独特的模型，该模型是基于GC B细胞中特定的DSB修复因子的有条件删除而建立的。我们建议使用我们独特的小鼠模型和新技术来阐明促进成熟B细胞易位和淋巴癌发生的机制：1)确定GC B细胞中DSB频率增加是否促进易患成熟B细胞淋巴瘤的易位；2)测试靶基因的空间邻近是否影响GC B细胞中的易位频率。我们的建议的完成将有助于更好地理解易位发生的具体过程，以及调节特定基因座形成易位倾向的机制。我们的研究还可能确定新的候选癌基因或肿瘤抑制基因，这些基因是克隆性易位的靶点，可能成为治疗的靶点。最后，对原代GC B细胞易位的综合分析将为易位的分子机制提供重要的新见解，并在DNA损伤和修复领域产生更广泛的影响。与公共卫生相关：人们普遍认为，染色体易位可以通过破坏肿瘤抑制基因、激活癌基因或产生异常融合蛋白来促进癌症的发展。此外，癌症类型特异的染色体易位常见于白血病和淋巴瘤，并在实体瘤中越来越多地发现，如前列腺癌的TMPRSS2-ETS易位和肺癌的ALK易位。在此背景下，我们提出的调查染色体易位的靶向机制的研究将产生更广泛的影响。阐明这些机制将有助于癌症的病因、诊断和治疗。

DESCRIPTION (provided by applicant): Most human mature B cell lymphomas appear derived from germinal center (GC) or post-GC B cells and often harbor clonal translocations involving immunoglobulin (Ig) and oncogenes. The GC is a special microenvironment formed by mature B cells in response to antigens, where B cells proliferate vigorously and Ig genes undergo two DNA alteration events, somatic hypermutation (SHM) and class switch recombination (CSR). While it has been proposed that DNA double strand breaks (DSBs) during SHM or CSR are the primary sources of chromosomal translocations in GC-derived B cell lymphomas, this point has never been directly addressed due to the lack of proper mouse models. There are a few nicely characterized mouse models for GC-derived B cell lymphomas. However, most of these models are based on constitutive expression of oncogenes via lymphocyte-specific regulatory regions, an approach that fails to generate tumors with clonal translocations. We present a novel and unique model that we established based on the conditional deletion of a DSB repair factor specifically in GC B cells. We propose to employ our unique mouse model and new techniques to elucidate the mechanisms promoting translocation and lymphomagenesis in mature B cells by: 1) determining whether increased frequency of DSBs in GC B cells promote translocations that predispose to mature B cell lymphomas; 2) testing whether spatial proximity of target loci influence the translocation frequency in GC B cells. The completion of our proposal will lead to better understanding of the specific processes during which translocations arise and the mechanisms that regulate the propensity of specific loci to form translocations. Our studies may also identify novel candidate oncogenes or tumor suppressor genes that are targeted by clonal translocations and could potentially serve as therapeutic targets. Finally, the comprehensive analysis of primary GC B cell translocations will provide major new insight into the molecular mechanism of translocation and have broader impact in the field of DNA damage and repair. Relevance to Public Health: It is widely accepted that chromosomal translocation can promote cancer development by disrupting tumor suppressors, activating oncogenes, or generating aberrant fusion proteins. Furthermore, cancer type-specific chromosomal translocations are frequently identified in leukemia and lymphomas, and increasingly found in solid tumors such as TMPRSS2-ETS translocation in prostate cancer and ALK translocations in lung cancer. In this context, our proposed studies to investigate targeting mechanisms for chromosomal translocations will have broader impacts. Elucidation of such mechanisms will shed light on the etiology, diagnosis and treatment of cancer.