PROGRAM PROJECT GRANT: Molecular Targets of Germinal Center B-Cell Lymphomas

描述（由申请方提供）：老年中心（GC）B细胞淋巴瘤是临床和遗传异质性疾病。近年来，最常见的GC B细胞淋巴瘤的发病率急剧增加，在上一代中增加了50%。本次PO 1的参与者认为，在这些日益常见的疾病中取得更多的重大突破将需要更全面地了解关键的潜在致病事件。出于这个原因，我们建议在这个竞争性更新申请中解决以下假设：1）DNA损伤修复和免疫球蛋白基因重排失调的缺陷易导致致癌易位和淋巴瘤的发展（F。Alt，Project 1）; 2）通过B细胞受体（BCR）途径的紧张性信号传导和典型和替代NFicB途径的组成性激活增加GC B细胞淋巴瘤的存活（K. Raidsky，Project 2）; 3）必需GC转录因子BCL 6的表达失调促进某些大B细胞淋巴瘤的发展（R. Dalla-Favera，项目3）; 4）大B细胞淋巴瘤的特定亚型具有独特的发病机制和合理的治疗靶点（M。Shipp，项目4）;和5）GC B细胞淋巴瘤中失调的凋亡和转录程序的组分可以使用称为烃钉合的新化学策略靶向（L. Walensky，Project 5）.拟议的项目在很大程度上依赖于以下核心研究人员的投入和合作：DNA微阵列/生物信息学（T。Golu B，核心A）、血液病理学（J. Aster，核心B）、生物统计学/临床试验（D. Neuberg/A. Freedman，Core C）和Administration（M. Shipp/K. Raubrsky，Core D）.在本PO 1中，我们将利用精心设计的GC B细胞淋巴瘤小鼠模型和高度信息化的原发性人类肿瘤和细胞系来定义这些疾病中最重要的分子事件。我们的长期目标是确定GC B细胞淋巴瘤发展的易感因素和分子基础，改善特定实体的诊断，完善我们的预后评估，并为更有效和更特异的治疗干预提供合理的靶点。

DESCRIPTION (provided by applicant): Germinal center (GC) B-cell lymphomas are clinically and genetically heterogeneous disorders. The incidence of the most common GC B-cell lymphomas has increased dramatically in recent years, with a 50 percent rise in the last generation. The participants of this PO1 believe that additional major breakthroughs in these increasingly common diseases will require a more complete understanding of critical underlying pathogenetic events. For this reason, we propose to address the following hypotheses in this competitive renewal application: 1) defects in DMA damage repair and deregulated immunoglobulin gene rearrangement predispose to oncogenic translocations and the development of lymphomas (F. Alt, Project 1); 2) tonic signaling via the B-cell receptor (BCR) pathway and constitutive activation of the canonical and alternative NFicB pathways increases the survival of GC B-cell lymphomas (K. Rajewsky, Project 2); 3) deregulated expression of the essential GC transcription factor, BCL6, promotes the development of certain large B-cell lymphomas (R. Dalla-Favera, Project 3); 4) specific subtypes of large B-cell lymphoma have unique pathogenetic mechanisms and, likely, rational therapeutic targets (M. Shipp, Project 4); and 5) components of deregulated apoptotic and transcriptional programs in GC B-cell lymphomas can be targeted using a novel chemical strategy termed hydrocarbon stapling (L. Walensky, Project 5). The proposed projects rely heavily on input of and collaboration with investigators in the following Cores: DNA Microarray/Bioinformatics (T. Golub, Core A), Hematopathology (J. Aster, Core B), Biostatistics/Clinical Trials (D. Neuberg/A. Freedman, Core C) and Administration (M. Shipp/K. Rajewsky, Core D). In this PO1, we will utilize carefully designed murine models of GC B-cell lymphomas and highly informative primary human tumors and cell lines to define the most important molecular events in these diseases. Our long-term goal is to identify predisposing factors and molecular bases for the development of GC B-cell lymphomas, improve the diagnosis of specific entities, refine our prognostic assessments and credential rational targets for more effective and specific therapeutic intervention.