Unraveling germinal center B cell lymphoma development

揭示生发中心 B 细胞淋巴瘤的发展

• 批准号: 7024987
• 负责人: VINCENT K TSIAGBE
• 金额: $ 27.93万
• 依托单位: UNIV OF MED/DENT OF NJ-NJ DENTAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-03-15 至 2008-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7024987
• 关键词: B cell lymphoma; B lymphocyte; CD4 molecule; Peyer' s patches; RNase protection assay; disease /disorder etiology; disease /disorder model; gene expression; gene expression profiling; genetically modified animals; laboratory mouse; microarray technology; monoclonal antibody; mouse mammary tumor virus; neoplasm /cancer genetics; neoplastic growth; northern blottings; pathologic process; polymerase chain reaction; protein isoforms; superantigens; transcription factor

DESCRIPTION (provided by applicant): Lymphomas of SJL and C57L mice are derived from germinal center (GC) B cells and resemble several human GC-derived lymphomas. These mouse and human lymphomas contain CD4+ T cells. The SJL and C57L mouse lymphomas express retroviral superantigen (vSAg29) encoded by endogenous mouse mammary tumor virus (Mtv29), which vigorously stimulates CD4 T cells bearing T cell receptor (TCR) BV16 family. The responding CD4 T cells produce growth factors, upon which the lymphomas depend for their proliferation. The vSAg29 mRNA is produced under the control of a promoter, MMTV envelope transcription activator (META-env), in the envelope region of Mtv29. Demethylation in this promoter region appears to be inevitable for the transcription of vSAg29. This promoter region has a binding site for the zinc-finger transcription factor, Ikaros, and the binding of Ikaros could results in the maintenance of condensed chromatin structure which would leads to transcriptional repression. However, SJL lymphomas over-express a non-DNA binding Ikaros isoform (Ik6) which has a dominant negative effect by relaxing chromatin, and thus permitting access of MMTV-env to transcription factors. Limited profile of gene expression shows that SJL lymphomas express unique set of lymphoma-specific genes. In aim 1, a more extensive analysis will be conducted using an updated mouse GeneChip expression set to find time-dependent progression of gene expression leading to lymphoma, by examining mice at different ages until onset of lymphoma. This study is expected to uncover the sequential genetic events leading to superantigen-driven lymphoma development. A sub-population of human lymphomas express surface CD30, which is a member of the "tumor necrosis factor receptor" family, and CD30 monoclonal antibodies (mAbs) are already in clinical trials for treatment of human lymphomas. However, there is little information on the mechanisms of action and the cellular target of these mAbs. In SJL mice, CD30 mAb blocks lymphoma development in vivo. In aim 2, SJL mice expressing CD30 as a transgene expressed in CD4 T cells, and mice null for either CD30 or for CD30L will be used to understand the mode of action of CD30 mAbs in lymphoma. In aim 3, studies will be conducted using mice transgenic for non-DNA binding isoform of Ikaros, in order to understand the role of Ik6 in lymphoma. The effect of this Ikarose transgene on age-depended induction of vSAg29 and lymphoma development will be examined. This finding is relevant to human lymphoma since the human genome is laden with endogenous retroviral genes (approximately 0.6%), some of which have the potential for transcription.

描述（由申请方提供）：SJL和C57 L小鼠的淋巴瘤来源于生殖中心（GC）B细胞，与几种人GC来源的淋巴瘤相似。这些小鼠和人类淋巴瘤含有CD 4 + T细胞。SJL和C57 L小鼠淋巴瘤表达由内源性小鼠乳腺肿瘤病毒（Mtv 29）编码的逆转录病毒超抗原（vSAg 29），其强烈刺激携带T细胞受体（TCR）BV 16家族的CD 4 T细胞。应答的CD 4 T细胞产生生长因子，淋巴瘤依赖于其增殖。vSAg 29 mRNA在启动子MMTV包膜转录激活因子（META-env）的控制下在Mtv 29的包膜区产生。该启动子区域的去甲基化对于vSAg 29的转录似乎是不可避免的。该启动子区域具有锌指转录因子Ikaros的结合位点，并且Ikaros的结合可导致浓缩的染色质结构的维持，这将导致转录抑制。然而，SJL淋巴瘤过表达非DNA结合Ikaros同种型（Ik 6），其通过松弛染色质具有显性负效应，从而允许MMTV-env接近转录因子。有限的基因表达谱表明，SJL淋巴瘤表达独特的一组淋巴瘤特异性基因。在目标1中，将使用更新的小鼠基因芯片表达集进行更广泛的分析，以通过检查不同年龄的小鼠直到淋巴瘤发作来发现导致淋巴瘤的基因表达的时间依赖性进展。这项研究有望揭示导致超抗原驱动的淋巴瘤发展的顺序遗传事件。人淋巴瘤的亚群表达表面CD 30，其是“肿瘤坏死因子受体”家族的成员，并且CD 30单克隆抗体（mAb）已经在临床试验中用于治疗人淋巴瘤。然而，关于这些mAb的作用机制和细胞靶点的信息很少。在SJL小鼠中，CD 30 mAb可阻断体内淋巴瘤发展。在目标2中，将使用表达作为在CD 4 T细胞中表达的转基因的CD 30的SJL小鼠和CD 30或CD 30 L缺失的小鼠来理解CD 30 mAb在淋巴瘤中的作用模式。在目标3中，将使用Ikaros的非DNA结合同种型转基因小鼠进行研究，以了解Ik 6在淋巴瘤中的作用。将检查该Ikarose转基因对vSAg 29的年龄依赖性诱导和淋巴瘤发展的影响。这一发现与人类淋巴瘤有关，因为人类基因组中含有内源性逆转录病毒基因（约0.6%），其中一些具有转录潜力。