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

TET 介导的表观遗传调控 B 细胞淋巴瘤的发生和免疫逃避

基本信息

批准号：
10242616
负责人：
Chan-Wang Jerry Lio
金额：
$ 16.18万
依托单位：
OHIO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-01 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10242616
关键词：
Address Affect Antibody Response B Cell Proliferation B-Cell Lymphomas B-Lymphocytes Bone Marrow CD4 Positive T Lymphocytes Cell Differentiation process Cell Survival Cell model Cells Chromatin Collaborations DNA Defect Deposition Development Dioxygenases EZH2 gene Elements Enhancers Enzymes Epigenetic Process Gene Expression Regulation Genes Goals Human Hyperplasia Immune response Immunization Immunooncology Immunotherapy Impairment In Vitro K22 Award Lead Light Link Lymphomagenesis Malignant - descriptor Malignant Neoplasms Mature B-Lymphocyte Mediating Molecular Mus Mutation Oxidases Oxides Pharmacology Phenotype Physiological Protein Dynamics Proteins Proteomics Research Personnel Role Structure of germinal center of lymph node System T cell response T-Lymphocyte Testing Tetanus Helper Peptide Therapeutic Training Tumor Suppression anti-cancer cell transformation demethylation epigenetic regulation epigenome follow-up in vivo insight large cell Diffuse non-Hodgkin&apos s lymphoma methyl group novel prevent recruit skills tool transcription factor transcriptome tumor

项目摘要

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.

抽象的表观基因组失调已成为癌症的标志。例如，80%以上的弥漫性大 B 细胞淋巴瘤 (DLBCL) 携带至少一种表观遗传调节因子突变，包括 TET2。 TET 蛋白质（10-11 易位；TET1、TET2、TET3）是氧化 5- 甲基的双加氧酶甲基胞嘧啶 (5mC) 主要转变为 5-羟甲基胞嘧啶 (5hmC)，这是一种稳定的表观遗传标记，也是一种重要的 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 蛋白如何抑制细胞转化尚不清楚。 Tet 突变导致 B 细胞增殖失调。出乎意料的是，B 细胞中的 TET 突变影响了反式 T 细胞，并产生了允许细胞转化的微环境。在这个 K22 提案中，我将把这些研究扩展到研究TET酶在调节GC B细胞表观基因组及其恶性中的作用转化为DLBCL。具体来说，我将检验 TET 蛋白预防 B 的假设淋巴瘤的发生是通过细胞内在调节 B 细胞的表观基因组和外在影响旁观者 T 细胞。为了解决这个假设，我提出以下具体目标。在目标 1 中，我将分析羟甲基化组并定义正常和转化的生发中心 B 细胞的 TetE 老鼠和人类。在 Aim2 中，我将研究 TET 和其他表观遗传之间的功能协作监管机构。我还将使用一种新颖的蛋白质组学方法来分析 TetEs 的位点特异性蛋白质组学。在目标 3 中，我将检查 Tet 缺陷 B 细胞和 T 细胞之间意外的串扰。这个 K22 提案将使我获得成为独立调查员所需的技能。完成本提案将提供对表观基因组失调与 B 细胞之间联系的分子机制有重要见解转变。最后，研究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。