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：
7240556
负责人：
Bihui Hilda Ye
金额：
$ 34.42万
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 2011-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7240556
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 Diffuse Lymphoma Exons Failure Feedback Gene Targeting Genes Genetic Genetic Transcription Grant Growth Histone Deacetylase Histones Homeostasis Immune system Knockout Mice Large-Cell Lymphomas Learning Lymphoid Lymphoma Lymphomagenesis Maps Modeling Modification Mutation NuRD complex POZ-zinc Pathway interactions Pattern Phenotype Plasma Cells Proteins Proto-Oncogenes Reaction Recruitment Activity Regulation Role Role playing therapy STAT3 gene Signal Pathway Staging Structure Structure of germinal center of lymph node System Testing Thinking Transcription Repressor/Corepressor Transgenic Mice Treatment outcome Universities Work Zinc Fingers cell type design 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

DESCRIPTION (provided by applicant): 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 repressor 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 STAT3 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 STAT3 in plasma cell differentiation, determine the cause of constitutive STAT3 activation in ABC-DLBCL, and study the tumorigenic potential of a constitutively activated STAT3 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 STAT3 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 STAT3 in the genetics and biology of B cell lymphomas.

描述（由申请人提供）：该项目的主要目标是了解 BCL-6 基因是如何调节的，以及它与 IL-6/STAT3 通路的功能性相互作用如何有助于其在正常 B 细胞和 B 细胞淋巴瘤中的作用。 BCL-6 编码 POZ-锌指型转录阻遏蛋白，被认为通过招募辅阻遏物 SMRT/NCoR/BCoR 和 NuRD/MTA3 来抑制体内转录。由于基因改变超越了控制 BCL-6 转录的负性自动调节机制，BCL-6 在许多弥漫性大细胞淋巴瘤 (DLBCL) 中持续高水平表达。在正常淋巴系统中，高水平的 BCL-6 蛋白专门存在于生发中心 (GC) 内的 B 细胞中，并且 BCL-6 功能对于 GC 的形成至关重要。我们最近的工作表明，BCL-6 自动调节以 SMRT/NCoR/BCoR 和 NuRD/MTA3 独立的方式发挥作用。因此，在目标 1 中，我们计划表征 BCL-6 自身调节中涉及的特定染色质变化，并确定 BCL-6 蛋白用于调节其自身转录的新型辅阻遏物。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 STAT3 表达/激活的强大抑制剂，并且 STATS 在 DLBCL (ABC-DLBCL) 等激活的 B 细胞中持续激活，并且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分化中 BCL6 和 STAT3 之间的功能关系，确定 ABC-DLBCL 中组成型 STAT3 激活的原因，并研究体内组成型激活的 STAT3 的致瘤潜力。由于 ABC-DLBCL 通常与不良治疗结果相关，因此我们还计划开展合作研究，以评估 STAT3 激活作为单一标志物或与 BCL6 组合在原发性 DLBCL 中的预后价值。我们的研究应该提供有关 BCL6 反式抑制机制的新方面的有价值的信息，更重要的是，进一步了解 BCL6 和 STAT3 在 B 细胞淋巴瘤的遗传学和生物学中所发挥的作用。