HYPERMUTATION OF BCL6 REGULATORY SEQUENCES IN NONHODGKIN'S LYMPHOMA

BCL 6基因编码锌指转录因子， 通过其5'非编码区的染色体重排， 大约30%的弥漫性大细胞淋巴瘤（DLCL）。 最近 结果表明，在大约73%的DLCL中。和 大约50%滤泡性淋巴瘤BLC 6基因也是 通过在其5'端非等位基因中聚集的多个，通常是双等位基因的突变改变， 编码区 这些突变是体细胞起源的，并在 显示正常或重排的BCL 6等位基因的病例表明 不受染色体重排的影响 总目标 本项目的目的是研究这些事件的发生机制， 突变及其在淋巴瘤发生中的作用。 特别是 将进行以下调查：1）BCL 6的机制 超突变 一些观察结果表明，BCL 6突变可能 与免疫球蛋白可变区的活性相关 (IgV)B细胞中的超突变机制。 为了调查这件事 问题，我们将比较分析IgV的突变频率 和BCL 6序列在：1）正常生殖中心B细胞ii）B细胞 衍生肿瘤，例如伯基特淋巴瘤、慢性淋巴细胞白血病， 显示不同IgV突变水平的多发性骨髓瘤，2） BCL 6超突变的功能后果。 由于BCL 6突变 聚集在BCL 6的5'非编码区，可以想象， 它们可能在肿瘤发生过程中被选择， BCL 6基因表达。 突变对BCL 6转录的影响 将在携带正常细胞的细胞系中研究启动和进展。 和突变型BCL 6等位基因以及通过转染野生型/和 突变体/报告基因构建体在适当的B细胞系中的表达。 3)作用 淋巴瘤发生中的BCL 6突变为了测试BCL 6突变是否 有助于淋巴瘤生成，携带NHL衍生的转基因小鼠 将构建突变体BCL 6等位基因。 将对这些小鼠进行以下研究： i）B细胞谱系发育; ii）肿瘤发育。 这些研究 应该提供深入了解发生机制和生物学 BCL 6突变的作用，最常见的遗传变异相关 非霍奇金淋巴瘤

The BCL6 gene encodes a zinc-finger transcription factor and is altered by chromosomal rearrangements in its 5' non-coding region in approximately 30 percent of diffuse large-cell lymphoma (DLCL). Recent findings indicate that in approximately 73 percent DLCL. and approximately 50 percent follicular lymphoma the BLC6 gene is also altered by multiple, often biallelic, mutations clustering in its 5' non- coding region. These mutations are of somatic origin and are found in cases displaying either normal or rearranged BCL6 alleles indicating their independence from chromosomal rearrangements. The general goal of this project is to investigate the mechanism of occurrence of these mutations and their role in lymphomagenesis. In particular, the following lines of investigations will be pursued: 1) Mechanism of BCL6 hypermutation. Several observations suggest that BCL6 mutations may be associated with the activity of the Immunoglobulin Variable region (IgV) hypermutation mechanism in B cells. In order to investigate this issue, we will comparatively analyze the frequency of mutation in IgV and BCL6 sequences in: 1) normal germinal-center B cells ii) B cell derived tumors such as Burkitt lymphoma, chronic lymphocytic leukemia, multiple myeloma which display different levels of IgV mutations, 2) Functional consequences of BCL6 hypermutation. Since BCL6 mutations are clustered in the 5' noncoding region of BCL6, it is conceivable that they may have been selected during tumorigenesis for a role in altering BCL6 gene expression. The effect of mutations on BCL6 transcription initiation and progression will be studied in cell lines carrying normal and mutant BCL6 alleles as well as by transfection of wild-type/and mutant/reporter gene constructs in appropriate B cells lines. 3) Role of BCL6 mutation in lymphomagenesis. To test whether BCL6 mutations contribute to lymphomagenesis, transgenic mice carrying NHL-derived mutant BCL6 alleles will be constructed. These mice will be studied for: i) B cell lineage development; ii) tumor development. These studies should provide insights into the mechanism of occurrence and biological role of BCL6 mutation, the most frequent genetic alteration associated with non-Hodgkin lymphoma.