Unraveling germinal center B cell lymphoma development

描述（由申请人提供）：SJL和C57L小鼠的淋巴瘤来源于生发中心（GC） B细胞，类似于几种人类GC来源的淋巴瘤。这些小鼠和人类淋巴瘤含有CD4+ T细胞。SJL和C57L小鼠淋巴瘤表达内源性小鼠乳腺肿瘤病毒（Mtv29）编码的逆转录病毒超抗原（vSAg29），能强烈刺激携带T细胞受体（TCR） BV16家族的CD4 T细胞。相应的CD4 T细胞产生生长因子，淋巴瘤依靠生长因子增殖。vSAg29 mRNA是在Mtv29包膜区域的启动子MMTV包膜转录激活子（META-env）的控制下产生的。这个启动子区域的去甲基化对于vSAg29的转录是不可避免的。这个启动子区域有一个锌指转录因子Ikaros的结合位点，Ikaros的结合可能导致染色质结构的维持，从而导致转录抑制。然而，SJL淋巴瘤过度表达一种非dna结合的Ikaros亚型（Ik6），其主要的负面作用是放松染色质，从而允许MMTV-env进入转录因子。有限的基因表达谱显示SJL淋巴瘤表达一组独特的淋巴瘤特异性基因。在目标1中，将使用更新的小鼠GeneChip表达集进行更广泛的分析，通过检查不同年龄的小鼠直到淋巴瘤发病，以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级抗原驱动淋巴瘤发展的顺序遗传事件。人类淋巴瘤的一个亚群表达表面CD30，它是“肿瘤坏死因子受体”家族的成员，CD30单克隆抗体（mab）已经在临床试验中用于治疗人类淋巴瘤。然而，关于这些单克隆抗体的作用机制和细胞靶点的信息很少。在SJL小鼠中，CD30 mAb在体内阻断淋巴瘤的发展。在目的2中，将CD30作为在CD4 T细胞中表达的转基因表达的SJL小鼠，以及CD30或CD30L缺失的小鼠，用于了解CD30单克隆抗体在淋巴瘤中的作用模式。在aim 3中，我们将使用转基因小鼠进行Ikaros非dna结合异构体的研究，以了解Ik6在淋巴瘤中的作用。这种伊卡罗斯转基因对年龄依赖性诱导vSAg29和淋巴瘤发展的影响将被检验。这一发现与人类淋巴瘤有关，因为人类基因组中充满了内源性逆转录病毒基因（约0.6%），其中一些具有转录潜力。

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.