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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.

该项目的主要目的是了解BCL-6基因是如何调节的，以及它的功能如何。与IL-6/STAT 3途径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编码一个POZ-锌指型转录抑制因子，被认为抑制转录通过募集辅阻遏物SMRT/NCoR/BCoR和NuRD/MTA 3在体内进行。BCL-6的组成型表达为在许多弥漫性大细胞淋巴瘤（DLBCL）中，由于基因改变，控制BCL-6转录的自身调节机制。在正常淋巴系统中，高水平的BCL-6 在生发中心（GC）内的B细胞中特异性发现一种蛋白质，BCL-6的功能对于GC至关重要阵我们最近的工作表明BCL-6的自动调节作用于SMRT/NCoR/BCoR-和 NuRD/MTA 3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BCL 6是一种 STATS表达/活化的强有力抑制剂，并且STATS在活化的细胞中组成性活化。 B细胞样DLBCL（ABC-DLBCL）是细胞增殖和存活所必需的。因此，目标2中的实验目的是研究浆细胞中BCL 6和STATS之间的功能关系，分化，确定ABC-DLBCL中组成性STATS激活的原因，并研究ABC-DLBCL中STATS的表达。组成型激活的STATS在体内的致瘤潜力。由于ABC-DLBCL通常与治疗结果不佳，我们还计划进行合作研究，以评估原发性DLBCL中的STATS活化作为单一标志物或与BCL 6组合。我们的研究应该提供关于BCL 6反式阻遏机制的新方面的有价值的信息，更重要的是，进一步了解BCL 6和STATS在遗传学中所起的作用， B细胞淋巴瘤生物学。