ROLE OF THE BCL 6 PROTO ONCOGENE IN B CELL LYMPHOMAS

BCL 6 原癌基因在 B 细胞淋巴瘤中的作用

• 批准号: 6514421
• 负责人: Bihui Hilda Ye
• 金额: $ 33.36万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-05-01 至 2005-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6514421
• 关键词: B cell lymphoma; B lymphocyte; apoptosis; carcinogenesis; cell proliferation; complementary DNA; gene induction /repression; gene mutation; genetically modified animals; laboratory mouse; microarray technology; protooncogene; transcription factor

DESCRIPTION: (Adapted from the investigator's abstract) Aggressive non Hodgkin's B-cell lymphomas often carry chromosomal translocations in the proto-oncogene BCL-6 locus. Translocations deregulate BCL-6 expression via promoter substitution, leading to constitutive high levels of the wild type BCL-6 protein in lymphoma B cells. In normal B cells, the BCL-6 protein is expressed only at the germinal center stage. BCL-6 is a zinc finger-containing transcription repressor. Knock out studies in mice have suggested important regulatory functions for BCL-6 in the immune system. Still, very little is known about how its expression is normally regulated in B as well as in non-B cells. In addition, the mechanism by which abnormal BCL-6 expression contributes to lymphomagenesis is still unclear. The first specific aim will attempt to characterize a negative autoregulatory mechanism governing BCL-6 transcription. Experiments are designed to first firmly establish its existence in B cells with a wild type BCL-6 gene. Its integrity in tumor B cells with genetically altered BCL-6 gene will then studied. In the second aim, we will test our hypothesis that continued expression of the BCL-6 protein is essential for maintaining the tumorigenicity of lymphoma cell lines. We will attempt to downregulate the activity of BCL-6 protein by expression of either the antisense or dominant negative BCL-6 mutants (knock down approach). Corresponding changes in the cellular phenotype of lymphoma cells will be studied. As our preliminary data suggests a role of BCL-6 in preventing apoptosis, identifying a link between BCL-6 and apoptosis regulators will be a priority. In the third aim, effort will be made to search for BCL-6 genes genes based upon this knock down approach. A combination of cDNA RDA and the cDNA microarray techniques will be used. The last specific aim is to establish the causative role of BCL-6 in lymphomagenesis in vivo by generating conditional BCL-6 transgenic mice using the cre-lox system. Phenotypes to be analyzed include germinal center enter function, B cell proliferation and tumorigenesis.

描述：（改编自研究者的摘要）攻击性非 霍奇金 B 细胞淋巴瘤通常携带染色体易位 原癌基因 BCL-6 位点。易位通过以下方式解除 BCL-6 表达的调节： 启动子取代，导致野生型的组成型高水平 淋巴瘤 B 细胞中的 BCL-6 蛋白。在正常 B 细胞中，BCL-6 蛋白是 仅在生发中心阶段表达。 BCL-6是一种含锌指的 转录抑制子。对小鼠的敲除研究表明重要 BCL-6 在免疫系统中的调节功能。尽管如此，还是很少 了解其表达在 B 和非 B 中通常是如何调节的 细胞。此外，BCL-6表达异常的机制 是否有助于淋巴瘤发生尚不清楚。第一个具体目标将 尝试描述 BCL-6 的负向自动调节机制 转录。实验的目的是首先牢固地证实它的存在 存在于带有野生型 BCL-6 基因的 B 细胞中。其在肿瘤 B 细胞中的完整性 然后将研究基因改变的 BCL-6 基因。在第二个目标中，我们将 检验我们的假设，即 BCL-6 蛋白的持续表达至关重要 用于维持淋巴瘤细胞系的致瘤性。我们将尝试 通过表达以下任一者下调 BCL-6 蛋白的活性 反义或显性失活 BCL-6 突变体（敲低方法）。 淋巴瘤细胞的细胞表型的相应变化将是 研究过。正如我们的初步数据表明 BCL-6 在预防 细胞凋亡，确定 BCL-6 和细胞凋亡调节因子之间的联系将是 优先事项。第三个目标，将努力寻找BCL-6基因 基于这种击倒方法。 cDNA RDA 和 cDNA 的组合 将使用微阵列技术。最后一个具体目标是建立 BCL-6通过产生条件在体内淋巴瘤发生中的致病作用 使用 cre-lox 系统的 BCL-6 转基因小鼠。待分析的表型 包括生发中心输入功能、B细胞增殖和肿瘤发生。