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

• 批准号: 10460237
• 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
• 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/10460237
• 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; Immunosuppression; 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' s lymphoma; methyl group; novel; prevent; recruit; skills; tool; transcription factor; transcriptome; tumor

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 表观基因组失调的表观成绩已成为癌症的标志。例如，超过80％的分散 大B细胞淋巴瘤（DLBCL）在包括TET2在内的至少一个表观遗传调节剂中携带突变。 tet 蛋白质（十个易位； TET1，TET2，TET3）是氧化5--甲基的二氧酶 甲基胞嘧啶（5MC）主要针对5-羟基环霉素（5HMC），稳定的表观遗传标记和必不可少的 DNA脱甲基化的中间体。尽管TET突变与癌症密切相关，但该机制 通过该蛋白质抑制细胞转化的情况尚不清楚。 TET突变导致 B细胞增殖失调。出乎意料的是，B细胞中的TET-MONT会影响Trans中的T细胞，并创建A 微环境允许细胞转化。在此K22提案中，我将将这些研究扩展到 研究TET酶在调节GC B细胞的表观基因组及其恶性肿瘤中的作用 转换为DLBCL。具体而言，我将测试TET蛋白预防B的假设 通过细胞间调节B细胞的表观基因组并外在影响淋巴作用 旁观者T细胞。为了解决这一假设，我提出了以下特定目标。在AIM 1中，我会 介绍羟基甲基甲基，并定义TETES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与其他表观遗传学之间的功能合作 监管机构。我还将使用一种新型的蛋白质组学方法来分析TETES的基因座特异性蛋白质组学。在AIM 3中， 我将检查缺乏TET缺陷的B细胞和T细胞之间的意外串扰。这个K22提案将允许我 获得必要的技能，成为独立研究者。该提案的完成将提供 对表观基因组失调与B细胞之间联系的分子机制的重要洞察力 转型。最后，结果可能会通过针对 表观遗传机制和/或通过调节抗癌免疫反应。

项目成果

Micro but mighty-Micronutrients in the epigenetic regulation of adaptive immune responses.

• DOI: 10.1111/imr.13045
• 发表时间: 2022-01
• 期刊: Immunological reviews
• 影响因子: 8.7
• 作者: Chen HY;Hsu M;Lio CJ
• 通讯作者: Lio CJ

Epigenetic remodeling by vitamin C potentiates plasma cell differentiation.

• DOI: 10.7554/elife.73754
• 发表时间: 2022-09-07
• 期刊: ELIFE
• 影响因子: 7.7
• 作者: Chen, Heng-Yi;Almonte-Loya, Ana;Lay, Fang-Yun;Hsu, Michael;Johnson, Eric;Gonzalez-Avalos, Edahi;Yin, Jieyun;Bruno, Richard S.;Ma, Qin;Ghoneim, Hazem E.;Wozniak, Daniel J.;Harrison, Fiona E.;Lio, Chan-Wang Jerry
• 通讯作者: Lio, Chan-Wang Jerry