HYPERMUTATION OF BCL6 REGULATORY SEQUENCES IN NONHODGKIN'S LYMPHOMA

BCL6基因编码一种锌指转录因子，并发生改变 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)。近期 研究结果表明，在大约73%的DLCL中。和 大约50%的滤泡性淋巴瘤BLC6基因也是 由多个，通常是双等位基因，聚集在其5‘非等位基因上的突变所改变 编码区。这些突变源于体细胞，并在 BCL6等位基因正常或重排的病例表明 它们不受染色体重排的影响。总目标是 本项目的主要目的是研究这些疾病的发生机制。 突变及其在淋巴增生症中的作用。尤其是， 将进行以下方面的调查：1)《基本法》6的机制 超突变。几项观察表明，bcl6突变可能 与免疫球蛋白可变区的活性有关 (IgV)B细胞高突变机制。为了调查这件事 问题，我们将对比分析免疫球蛋白病毒的突变频率 和BCL6序列：1)正常生发中心B细胞II)B细胞 衍生肿瘤，如Burkitt淋巴瘤，慢性淋巴细胞白血病， 表现不同程度IgV突变的多发性骨髓瘤，2) Bcl6超突变的功能后果。由于BCL6突变 都聚集在BCL6的5‘非编码区，可以想象到 它们可能是在肿瘤发生过程中被选中的，在改变 Bcl6基因表达。突变对bcl6转录的影响 将在携带正常人的细胞系中研究启动和进展 和突变的bcl6等位基因，以及通过野生型/和 突变/报告基因在合适的B细胞系中构建。3)角色 淋巴瘤发生中的Bcl6突变。以检测bcl6突变是否 携带非霍奇金淋巴瘤来源的转基因小鼠有助于淋巴肿大 将构建突变的BCL6等位基因。这些小鼠将被研究： I)B细胞谱系的发展；ii)肿瘤的发展。这些研究 应该提供对发生机制和生物学的洞察 最常见的基因突变--bcl6突变的作用 患有非霍奇金淋巴瘤。

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.