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

基本信息

批准号：
7767766
负责人：
Bihui Hilda Ye
金额：
$ 36.5万
依托单位：
ALBERT EINSTEIN COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2000
资助国家：
美国
起止时间：
2000-05-01 至 2012-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7767766
关键词：
Address Adhesions B-Cell Lymphoma 6 Protein B-Cell Lymphomas B-Cell NonHodgkins Lymphoma B-Lymphocytes BCL1 Oncogene BCL6 gene Binding Sites Biological Models Biological Process Biology Bypass Cell Aging Cell Proliferation Chromatin Chromosomal translocation Collaborations Complex Diffuse Large-Cell Lymphoma Exons Failure Feedback Gene Targeting Genes Genetic Genetic Transcription Grant Growth Histone Deacetylase Homeostasis Immune system Knockout Mice Learning Lymphoid Lymphoma Lymphomagenesis Maps Modeling Mutation NuRD complex POZ-zinc Pathway interactions Pattern Phenotype Plasma Cells Play Proteins Proto-Oncogenes Reaction Recruitment Activity Regulation Role STAT3 gene Signal Pathway Staging Structure Structure of germinal center of lymph node System Testing Transgenic Mice Treatment outcome Universities Work Zinc Fingers cell type design histone modification in vivo inhibitor/antagonist interest large cell Diffuse non-Hodgkin&apos s lymphoma macrophage mutant novel outcome forecast plasma cell differentiation prognostic promoter research study response tumorigenic

项目摘要

The main objective of this project is to understand how the BCL-6 gene is regulated and how its functional interaction with the IL-6/STAT3 pathway may contribute to its role in normal B cells and B cell lymphomas. BCL-6 encodes a POZ-zinc finger type transcription represser that has been thought to repress transcription in vivo by recruiting corepressors SMRT/NCoR/BCoR and NuRD/MTA3. BCL-6 is constitutively expressed at high levels in many diffuse large cell lymphomas (DLBCL) due to genetic alterations that override a negative autoregulatory mechanism governing BCL-6 transcription. In the normal lymphoid system, high level BCL-6 protein is specifically found in B cells within the germinal centers (GC) and BCL-6 function is critical for GC formation. Our recent work indicates that BCL-6 autoregulation works in a SMRT/NCoR/BCoR-and NuRD/MTA3 independent manner. Therefore in Aim 1, we plan to characterize specific chromatin changes involved in BCL-6 autoregulation and identify the novel corepressor used by the BCL-6 protein to regulate its own transcription. Our recent study also uncovered a set of very novel findings indicating that BCL6 is a powerful inhibitor of STATS expression/activation, and that STATS is constitutively activated in the activated B cell like DLBCL (ABC-DLBCL) and required for cell proliferation and survival. Thus, experiments in Aim 2 are designed to characterize the functional relationship between BCL6 and STATS in plasma cell differentiation, determine the cause of constitutive STATS activation in ABC-DLBCL, and study the tumorigenic potential of a constitutively activated STATS in vivo. Since ABC-DLBCL is often associated with poor treatment outcome, we also plan to pursue collaborative studies to evaluate the prognostic value of STATS activation in primary DLBCL either as a single marker or in combination with BCL6. Our studies should provide valuable information regarding a novel aspect of BCL6's transrepression mechanism and more importantly, further our understanding of the roles played by BCL6 and STATS in the genetics and biology of B cell lymphomas.

该项目的主要目标是了解 BCL-6 基因是如何调控的以及其功能如何发挥作用。与 IL-6/STAT3 通路的相互作用可能有助于其在正常 B 细胞和 B 细胞淋巴瘤中的作用。 BCL-6 编码 POZ-锌指型转录抑制子，人们认为它可以抑制转录通过募集辅阻遏物 SMRT/NCoR/BCoR 和 NuRD/MTA3 进行体内实验。 BCL-6 组成型表达于由于基因改变覆盖了阴性结果，许多弥漫性大细胞淋巴瘤 (DLBCL) 中的高水平控制 BCL-6 转录的自动调节机制。在正常淋巴系统中，BCL-6 水平高蛋白质专门存在于生发中心 (GC) 内的 B 细胞中，BCL-6 功能对于 GC 至关重要形成。我们最近的工作表明 BCL-6 自动调节在 SMRT/NCoR/BCoR 中起作用，并且 NuRD/MTA3 独立方式。因此，在目标 1 中，我们计划表征特定的染色质变化参与 BCL-6 自身调节并鉴定 BCL-6 蛋白用于调节其自身的新型辅阻遏物自己的转录。我们最近的研究还发现了一系列非常新颖的发现，表明 BCL6 是一种 STATS 表达/激活的强大抑制剂，并且 STATS 在激活的 B 细胞如 DLBCL (ABC-DLBCL)，是细胞增殖和存活所必需的。因此，目标 2 中的实验旨在表征浆细胞中 BCL6 和 STATS 之间的功能关系分化，确定 ABC-DLBCL 中组成型 STATS 激活的原因，并研究体内组成型激活的 STATS 的致瘤潜力。由于 ABC-DLBCL 通常与治疗结果不佳，我们还计划进行合作研究来评估预后价值原发性 DLBCL 中的 STATS 激活可作为单一标记物或与 BCL6 组合使用。我们的研究应提供有关 BCL6 反式抑制机制的新颖方面的有价值的信息，并且更重要的是，进一步了解 BCL6 和 STATS 在遗传学和 B 细胞淋巴瘤的生物学。