Defining mechanisms of gammaherpesvirus-driven genomic instability in B cells

定义 B 细胞中伽马疱疹病毒驱动的基因组不稳定性的机制

基本信息

批准号：
10590669
负责人：
James Craig Forrest
金额：
$ 36.06万
依托单位：
UNIV OF ARKANSAS FOR MED SCIS
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-04-04 至 2027-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10590669
关键词：
Adult African Burkitt&apos s lymphoma Agonist Animal Model Animals Apoptosis B Cell Proliferation B-Cell Development B-Cell Lymphomas B-Lymphocytes C-Myc Translocation Cancer Etiology Cell Cycle Progression Cell Differentiation process Cell Proliferation Cell Survival Cells Chromosomal translocation Chronic DNA Damage DNA Repair DNA Sequence Alteration DNA Tumor Viruses Data Defense Mechanisms Dependence Development Disease Epstein-Barr Virus-Related Lymphoma Epstein-Barr virus LMP-1 protein Event Funding Genes Genetic Genome Genomic Instability Goals Heavy-Chain Immunoglobulins Homologous Gene Human Human Herpesvirus 4 Human Herpesvirus 8 IRF4 gene Incidence Infection Integration Host Factors Lymphocyte Lymphoma Lymphomagenesis Malaria Malignant Neoplasms Mediating Membrane Proteins Molecular Mus Mutate Mutation Oncogenes Parasites Pathogenesis Pathway interactions Plasmodium Plasmodium berghei Process Proliferating Proteins Publishing Reaction Resistance Risk Rodent Structure of germinal center of lymph node System Systems Analysis TP53 gene Testing Thymic Lymphoma Viral Viral Genes Viral Proteins Virus Virus Latency Work c-myc Proto-Oncogenes cell type chronic infection co-infection experimental study gammaherpesvirus human pathogen in vivo in vivo evaluation infected B cell innovation knockout gene latent infection metaplastic cell transformation novel therapeutic intervention pathogen prevent promoter response sarcoma synergism targeted treatment tumor tumorigenesis

项目摘要

PROJECT SUMMARY Gammaherpesviruses (GHVs) establish lifelong chronic infections that place the host at risk for numerous cancers. During chronic infection, GHVs express viral gene products that stimulate host-cell proliferation and differentiation, processes thought to facilitate long-term latent persistence and contribute to tumorigenesis. However, GHVs are not acutely transforming, and cancer is rare given the high incidence of infection among adult humans, estimated at more than 95% for Epstein-Barr virus (EBV). This suggests that host cells are equipped with an intrinsic resistance to GHV-driven proliferation and cellular immortalization. In work performed during the previous funding period, we identified the tumor suppressor p53 as a protein that is activated during the establishment of GHV latent infection. p53 is frequently considered a “guardian of the genome”, working downstream of multiple mutagenic pathways to halt cell-cycle progression, stimulate DNA repair, or promote apoptosis. p53 is frequently mutated in human cancers, including endemic Burkitt lymphoma, an EBV-associated lymphoma that is characterized by a chromosomal translocation between the immunoglobulin heavy-chain promoter and cellular proto-oncogene c-myc. It is hypothesized that EBV synergizes with malaria, to promote the survival of cells that harbor IgH/c-myc translocations. Using murine gammaherpesvirus 68 (MHV68) infection of mice as a small animal model to enable a multi-system analysis GHV pathogenesis, we demonstrated that p53 limits cellular proliferation, especially of germinal center (GC) cells. We also found that p53 inhibits IgH/c- myc translocations in B cells of infected mice, an event that correlates with enhanced B cell lymphoma development in p53-deficient mice infected with MHV68. Moreover, we provide preliminary data indicating that co-infection of mice with MHV68 and a murine malaria parasite also promotes IgH/c-myc translocations. Experiments proposed in this competing renewal will build on our previous progress, harnessing the powerful mouse and MHV68 genetic systems, to (i) define viral genes and molecular pathways that promote genomic instability and lymphoma development, (ii) identify viral and host-factor dependencies in GHV-driven lymphomas, and (iii) determine the mechanisms through which MHV68 and murine Plasmodium parasites facilitate chromosomal translocations. In addition to providing a better understanding of how GHVs cause disease, we anticipate that results of this work will inform new therapeutic approaches that target lymphoma dependencies and reduce the mutagenic potential of GHVs and related co-infections.

项目概要伽马疱疹病毒 (GHV) 会造成终生慢性感染，使宿主面临多种疾病的风险。在慢性感染期间，GHV 表达刺激宿主细胞增殖和增殖的病毒基因产物。分化，被认为促进长期潜在持续并有助于肿瘤发生的过程。然而，GHV 并没有急剧转变，而且由于感染率高，癌症很少见。成人中，估计超过 95% 的人感染 Epstein-Barr 病毒 (EBV)，这表明宿主细胞存在感染。在工作中具有对 GHV 驱动的增殖和细胞永生化的内在抵抗力。在之前的资助期间，我们发现肿瘤抑制因子 p53 是一种在 GHV 潜伏感染的建立通常被认为是“基因组的守护者”。多种诱变途径的下游，以阻止细胞周期进程、刺激 DNA 修复或促进 p53 在人类癌症中经常发生突变，包括地方性伯基特淋巴瘤（一种与 EB 病毒相关的疾病）。淋巴瘤的特征是免疫球蛋白重链之间的染色体易位重新认识到EBV与疟疾有协同作用，促进细胞原癌基因c-myc。使用鼠伽马疱疹病毒 68 (MHV68) 感染来观察携带 IgH/c-myc 易位的细胞的存活。小鼠作为小动物模型，以便能够进行多系统分析 GHV 发病机制，我们证明了 p53 限制细胞增殖，尤其是生发中心 (GC) 细胞的增殖。我们还发现 p53 抑制 IgH/c-。受感染小鼠 B 细胞中的 myc 易位，这一事件与增强型 B 细胞淋巴瘤相关此外，我们提供了初步数据表明，感染 MHV68 的 p53 缺陷小鼠的发育。小鼠同时感染 MHV68 和鼠疟原虫也会促进 IgH/c-myc 易位。在这次竞争更新中提出的实验将建立在我们之前的进展的基础上，利用强大的小鼠和 MHV68 遗传系统，以 (i) 定义促进基因组的病毒基因和分子途径不稳定性和淋巴瘤的发展，(ii) 确定 GHV 驱动的淋巴瘤中的病毒和宿主因子依赖性， (iii) 确定 MHV68 和鼠疟原虫寄生虫促进的机制除了更好地了解 GHV 如何引起疾病之外，我们还对染色体易位进行了研究。预计这项工作的结果将为针对淋巴瘤依赖性的新治疗方法提供信息并降低 GHV 和相关合并感染的致突变潜力。