ROLE OF THE BCL 6 PROTO ONCOGENE IN B CELL LYMPHOMAS

描述：(改编自调查员的摘要)咄咄逼人的 霍奇金B细胞淋巴瘤常伴有染色体易位 原癌基因bcl6基因座。易位通过以下途径解除bcl6的表达 启动子替换，导致野生型的结构性高水平 淋巴瘤B细胞中bcl6蛋白的表达。在正常的B细胞中，bcl6蛋白是 仅在生发中心阶段表达。BCL-6是一种含锌指的 转录抑制因子。对小鼠的基因敲除研究表明 BCL-6在免疫系统中的调节功能。尽管如此，几乎没有什么 已知其在B和非B中的表达通常是如何调节的 细胞。此外，bcl6异常表达的机制 对淋巴增生症的作用仍不清楚。第一个具体目标是 试图刻画一种调控bcl6的负性自我调节机制 抄写。实验的设计是为了首先确定它的存在 在携带野生型bcl6基因的B细胞中。其在肿瘤B细胞中的完整性 然后将对转基因的bcl6基因进行研究。在第二个目标中，我们将 测试我们的假设，即bcl6蛋白的持续表达是必不可少的 以维持淋巴瘤细胞系的致瘤性。我们将尝试 下调bc1-6蛋白活性的途径 反义或显性阴性bcl6突变体(敲击法)。 淋巴瘤细胞表型的相应变化将是 学习。正如我们的初步数据显示，bcl6在预防 细胞凋亡，确定bcl6和细胞凋亡调节因子之间的联系将是一个 优先考虑。在第三个目标中，将努力寻找bcl6基因。 基于这种推倒方法。CDNARDA与cDNA1的结合 将使用微阵列技术。最后一个具体目标是建立 BCL-6通过产生条件性细胞因子在体内淋巴组织增生性疾病中的作用 使用cre-lox系统的bcl6转基因小鼠。待分析的表型 包括生发中心进入功能、B细胞增殖和肿瘤发生。

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.