TET-mediated Epigenetic Regulation in the Development and Immunoevasion of B cell Lymphoma

摘要 表观基因组调控失调已成为癌症的标志。例如，超过80%的漫反射 大B细胞淋巴瘤(DLBCL)至少携带一个表观遗传调节因子的突变，包括TET2。泰特 蛋白质(Ten-Eleven易位；TET1、TET2、TET3)是氧化5-11甲基的双加氧酶。 甲基胞嘧啶(5mC)主要为5-羟甲基胞嘧啶(5hmC)，是一个稳定的表观遗传标记和必需的 DNA去甲基化的中间体。尽管Tet突变与癌症密切相关，但其机制 Tet蛋白是如何抑制细胞转化的还不是很清楚。Tet基因突变导致 B细胞增殖失调。出乎意料的是，B细胞中的Tet突变会影响反式T细胞，并产生 允许细胞转化的微环境。在这项K22提案中，我将把这些研究扩展到 Tet酶在GC-B细胞及其恶性表观基因组调控中的作用 转变为DLBCL。具体地说，我将测试Tet蛋白质阻止乙型病毒性肝炎的假设 细胞对B细胞表观基因组的内在调控和外在影响 旁观者T细胞。为了解决这一假设，我提出了以下具体目标。在《目标1》中，我将 分析羟甲基组并确定正常和转化的生发中心B细胞 老鼠和人类。在AIM2中，我将研究Tet和其他表观遗传学之间的功能协作 监管者。我还将使用一种新的蛋白质组学方法来分析TETES的特定基因位点蛋白质组学。在《目标3》中， 我将研究缺乏Tet的B细胞和T细胞之间的意外串扰。这份K22提案将允许我 获得成为独立调查员所需的技能。完成这项提案将提供 表观基因组失调与B细胞关系的分子机制研究 转型。最后，这一结果可能会导致针对癌症的治疗策略 表观遗传机制和/或通过调节抗癌免疫反应。

Abstract Dysregulated epigenome has emerged as the hallmark of cancers. For instance, more than 80% of diffuse large B cell lymphoma (DLBCL) carries the mutation in at least one epigenetic regulator, including TET2. TET proteins (Ten-Eleven Translocation; TET1, TET2, TET3) are dioxygenases that oxidize the methyl group of 5- methylcytosine (5mC) primarily to 5-hydroxymethylcytosine (5hmC), a stable epigenetic mark and an essential intermediate for DNA demethylation. Despite TET mutation strongly associates with cancers, the mechanism by which TET proteins suppress cell transformation is not well understood. Mutation of Tet resulted in dysregulated B cell proliferation. Unexpectedly, TET-mutation in B cells affects T cells in trans and creates a microenvironment permissive to cell transformation. In this K22 proposal, I will extend these studies to investigate the role of TET enzymes in regulating the epigenome of GC B cells and their malignant transformation into DLBCL. Specifically, I will test the hypothesis that TET proteins prevent B lymphomagenesis by cell-intrinsically regulating the epigenome of B cells and extrinsically affecting the bystander T cells. To address this hypothesis, I propose the following Specific Aims. In Aim 1, I will profile the hydroxymethylome and define the TetEs normal and transformed germinal center B cells from mouse and human. In Aim2, I will investigate the functional collaboration between TET and other epigenetic regulators. I will also use a novel proteomics approach to analyze locus-specific proteomics at TetEs. In Aim 3, I will examine unexpected crosstalk between Tet-deficient B cells and T cells. This K22 proposal will allow me to acquire the necessary skills to be an independent investigator. Completion of this proposal will provide significant insight into the molecular mechanism in the link between epigenome dysregulation and B cell transformation. Finally, the results will likely lead to the therapeutic strategies for cancer by targeting the epigenetic machinery and/or by modulating the anti-cancer immune response.