ROLE OF THE BCL 6 PROTO ONCOGENE IN B CELL LYMPHOMAS

描述：（改编自研究者摘要）攻击性非 何杰金氏B细胞淋巴瘤经常携带染色体易位， 原癌基因BCL-6位点。易位通过以下途径解除BCL-6表达的调节 启动子替换，导致野生型的组成性高水平 淋巴瘤B细胞中BCL-6蛋白。在正常的B细胞中，BCL-6蛋白是 只在中央舞台表现出来。BCL-6是一种含锌指蛋白， 转录抑制子小鼠基因敲除研究表明， BCL-6在免疫系统中的调节功能。不过， 已知其表达在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 对淋巴瘤发生的影响尚不清楚。第一个具体目标将 试图描述一个负性的自身调节机制，控制BCL-6 转录。实验的目的是首先确定它的存在 在具有野生型BCL-6基因的B细胞中。它在肿瘤B细胞中的完整性 然后研究基因改变的BCL-6基因。第二个目标，我们将 验证我们的假设，即BCL-6蛋白的持续表达是必要的， 用于维持淋巴瘤细胞系的致瘤性。我们将尝试 BCL-6蛋白的活性下调， 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 研究了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一个新的研究方向。 要务第三个目标是寻找BCL-6基因 基于这种击倒的方法。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.