Towards a Mouse Model of Classical Hodgkin's Disease and PTLD

建立经典霍奇金病和 PTLD 的小鼠模型

• 批准号: 8220847
• 负责人: Frederick W. Alt
• 金额: $ 50.14万
• 依托单位: IMMUNE DISEASE INSTITUTE, INC.
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-07-01 至 2012-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8220847
• 关键词: Ablation; Address; Affect; Animals; Antigens; Apoptosis; Apoptotic; B-Cell Development; B-Lymphocytes; Berlin; Blast Cell; Candidate Disease Gene; Cell Proliferation; Cell Survival; Cells; Cessation of life; Characteristics; Clinical; Collaborations; Complement; Development; Disease; Disease Progression; EBV-associated disease; Epstein-Barr Virus Infections; Event; Extinction (Psychology); Family; Funding; Gene Expression; Gene Targeting; Generations; Genes; Goals; Hematopoietic; Hodgkin Disease; Human; Human Herpesvirus 4; Hyperplasia; Immune system; Immunoglobulin Genes; Immunoglobulin Somatic Hypermutation; Immunologic Surveillance; Immunosuppression; JUN gene; LMP1; Laboratories; Letters; Light; Lymphoma; Lymphomagenesis; Lymphoproliferative Disorders; MSC gene; Malignant - descriptor; Mature B-Lymphocyte; Mediating; Membrane Proteins; Modeling; Molecular Medicine; Morbidity - disease rate; Mus; Mutate; Mutation; Myelogenous; NF-kappa B; Pathogenesis; Patients; Phenotype; Play; Proteins; Publications; Receptor Cell; Receptor Signaling; Receptors, Antigen, B-Cell; Reed-Sternberg Cells; Reed-Sternberg-like Cell; Role; STAT5A gene; Somatic Mutation; Specific qualifier value; Structure of germinal center of lymph node; System; T-Cell Depletion; T-Lymphocyte; TNFRSF5 gene; Transcription Factor AP-1; Transplantation; Up-Regulation; Viral Proteins; Western World; Work; Writing; base; cancer cell; cell transformation; improved; in vivo; infected B cell; metaplastic cell transformation; model development; mortality; mouse model; mutant; novel therapeutics; progenitor; programs; protein expression; public health relevance; receptor; receptor expression; research study; tool; transcription factor; Ablation; Address; Affect; Animals; Antigens; Apoptosis; Apoptotic; B-Cell Development; B-Lymphocytes; Berlin; Blast Cell; Candidate Disease Gene; Cell Proliferation; Cell Survival; Cells; Cessation of life; Characteristics; Clinical; Collaborations; Complement; Development; Disease; Disease Progression; EBV-associated disease; Epstein-Barr Virus Infections; Event; Extinction (Psychology); Family; Funding; Gene Expression; Gene Targeting; Generations; Genes; Goals; Hematopoietic; Hodgkin Disease; Human; Human Herpesvirus 4; Hyperplasia; Immune system; Immunoglobulin Genes; Immunoglobulin Somatic Hypermutation; Immunologic Surveillance; Immunosuppression; JUN gene; LMP1; Laboratories; Letters; Light; Lymphoma; Lymphomagenesis; Lymphoproliferative Disorders; MSC gene; Malignant - descriptor; Mature B-Lymphocyte; Mediating; Membrane Proteins; Modeling; Molecular Medicine; Morbidity - disease rate; Mus; Mutate; Mutation; Myelogenous; NF-kappa B; Pathogenesis; Patients; Phenotype; Play; Proteins; Publications; Receptor Cell; Receptor Signaling; Receptors, Antigen, B-Cell; Reed-Sternberg Cells; Reed-Sternberg-like Cell; Role; STAT5A gene; Somatic Mutation; Specific qualifier value; Structure of germinal center of lymph node; System; T-Cell Depletion; T-Lymphocyte; TNFRSF5 gene; Transcription Factor AP-1; Transplantation; Up-Regulation; Viral Proteins; Western World; Work; Writing; base; cancer cell; cell transformation; improved; in vivo; infected B cell; metaplastic cell transformation; model development; mortality; mouse model; mutant; novel therapeutics; progenitor; programs; protein expression; public health relevance; receptor; receptor expression; research study; tool; transcription factor

DESCRIPTION (provided by applicant): In Hodgkin's Disease (HD), the most common lymphoma in the Western world, the malignant cells are the so-called Hodgkin and Reed-Sternberg (HRS) cells, comprising only a few percent of the lymphoma mass. HRS cells are often infected by Epstein-Barr-Virus (EBV) and express the EBV proteins LMP1 and LMP2A, partially mimicking constitutively an active CD40 co-receptor and B cell antigen receptor (BCR), respectively. Previous work, which had identified somatically mutated B cells, often bearing mutations "crippling" BCR expression, as HRS progenitors, led to a scenario of HD pathogenesis, in which HRS cells derive from pre-apoptotic GC B cells rescued by LMP2A and LMP1 expression. Despite their B cell origin, HRS cells have largely lost the B cell-specific gene expression program and acquired expression of genes typical for the T and/or myeloid hematopoietic lineages. We hypothesize that this lineage infidelity is dictated by the interference of certain transcription factors (TFs) known to be expressed in HRS cells, namely Id2, ABF1 and Notch1, with the B cell- specific gene expression program. This together with constitutive expression of proteins promoting cell survival and proliferation, like the TF c-Jun and TFs of the NF-kB family, may ultimately reprogram GC B cells into HRS cells. In this general scenario, EBV infection is a major initial transforming event in HD, and is indeed known to result in up-regulation of the TFs NF-kB, AP1, Id2 and ABF1 in B cells. Following this general hypothesis, we have developed a strategy to target the expression of candidate genes into GC B cells, using Cre-mediated conditional gene targeting. Using and further improving these tools, we plan to analyze whether induced expression of the various EBV-derived proteins and TFs individually and in combination in GC B cells will result in trans-differentiation and transformation of those cells as it is seen in HRS cells in HD. Our ultimate goal is to generate a mouse model of HD and to better understand the role of cellular reprogramming in lymphomagenesis. A second EBV-associated disease addressed in the present proposal is Post-Transplant Lymphoproliferative Disorder (PTLD), common in post-transplantation patients and due to a significant extent to the outgrowth of EBV-infected B cells because of immune suppression. We have found that induced expression of the EBV protein LMP1, known to be a major player in EBV-mediated B cell transformation, in developing B cells in the mouse leads to the rejection of these cells by the immune system. Depletion of T cells in the animals results in the rapid outgrowth of LMP1 expressing B cell blasts and death of the mice within a few weeks. We plan to develop this system into a first mouse model of PTLD, by targeting LMP1 expression into mature B cells, and to fully characterize disease progression and reversibility in the mutant animals, with a view of ultimately using this model for the development of new therapeutic strategies. Public Health Relevance: Hodgkin's Disease (HD) is the most common lymphoma in the Western world, and Post-Transplant Lymphoproliferative Disorder (PTLD) is an important cause of morbidity and mortality in post-transplantation patients, posing a significant clinical problem. Epstein-Barr-Virus (EBV) plays a major role in both HD and PTLD, with almost half of the HD cases and most of PTLDs being associated with it. The present proposal is based on known features of the pathogenesis of these diseases in the human and extensive own work, and aims at the generation of EBV-related mouse models of HD and PTLD, which so far do not exist, but should open the way to new therapeutic strategies and also shed new light on the role of gene expression reprogramming in lymphomagenesis.

描述（由申请人提供）：在霍奇金氏病（HD）中，是西方世界中最常见的淋巴瘤，恶性细胞是所谓的霍奇金和芦苇 - 塞尔伯格（HRS）细胞，仅占淋巴瘤量的百分之几。 HRS细胞通常被Epstein-Barr-Virus（EBV）感染，并表达EBV蛋白LMP1和LMP2A，部分模仿了活性CD40共受体受体和B细胞抗原受体（BCR）。先前的工作已经鉴定出体形突变的B细胞，通常带有突变“残废”的BCR表达，如HRS祖细胞，导致了HD发病机理的情况，其中HRS细胞从LMP2A和LMP1表达的HRS细胞中得出。尽管具有B细胞的起源，但HRS细胞在很大程度上已经失去了B细胞特异性基因表达程序，并获得了T和/或髓样造血谱系的典型基因表达。我们假设这种谱系不忠性是由已知在HRS细胞中已知的某些转录因子（TF）的干扰决定了B细胞特异性基因表达程序的ID2，ABF1和Notch1。这与促进细胞存活和增殖的蛋白质的本构表达一样，例如NF-KB家族的TF C-JUN和TFS，最终可能会将GC B细胞重新编程为HRS细胞。在这种一般情况下，EBV感染是HD中的主要初始转换事件，实际上已知会导致B细胞中TFS NF-KB，AP1，ID2和ABF1的上调。遵循这一一般假设，我们采用了CRE介导的条件基因靶向，制定了一种靶向候选基因在GC B细胞中的表达的策略。使用并进一步改进这些工具，我们计划分析诱导的各种EBV衍生的蛋白质和TF的表达是否单独和GC B细胞中的组合将导致在HD中HRS细胞中看到的这些细胞的反差异和转化。我们的最终目标是生成HD小鼠模型，并更好地了解细胞重编程在淋巴细胞内的作用。本提案中解决的第二种与EBV相关的疾病是移植后淋巴细胞增生性疾病（PTLD），在移植后患者中常见，并且由于免疫抑制而导致EBV感染的B细胞的生长很大。我们发现，诱导的EBV蛋白LMP1的表达，已知是EBV介导的B细胞转化的主要参与者，在小鼠中发育的B细胞中导致免疫系统拒绝这些细胞。动物中T细胞的耗竭导致LMP1在几周内表达B细胞爆炸的快速生长和小鼠死亡。我们计划通过将LMP1表达靶向成熟的B细胞，并充分表征突变动物中的疾病进展和可逆性，从而将该系统开发为PTLD的第一个小鼠模型，并最终将这种模型用于开发新的治疗策略。公共卫生相关性：霍奇金氏病（HD）是西方世界中最常见的淋巴瘤，移植后淋巴增生性疾病（PTLD）是转移后患者发病率和死亡率的重要原因，带来了重大的临床问题。 Epstein-Barr-Virus（EBV）在HD和PTLD中都起着重要作用，其中几乎一半的HD病例和大多数PTLD都与之相关。本提案基于人类和广泛的工作中这些疾病的发病机理的已知特征，旨在生成与EBV相关的HD和PTLD的小鼠模型，到目前为止尚不存在，但应该为新的治疗策略开辟道路，并为基因表达在淋巴机中的作用而开发新的光明。