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

描述(申请人提供)：生发中心(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上升，上一代上升了50%。本次会议的与会者认为，在这些日益常见的疾病方面取得更多重大突破，将需要对关键的潜在致病事件有更全面的了解。为此，我们建议在这一竞争性更新应用中解决以下假设：1)DNA损伤修复缺陷和免疫球蛋白基因重排失控易于致癌易位和淋巴瘤的发展(F.Alt，项目1)；2)通过B细胞受体(BCR)途径的紧张性信号以及规范和替代NFicB通路的结构性激活增加GC B细胞淋巴瘤的存活率(K.Rajeski，项目2)；3)必要的GC转录因子BCL6的失控表达促进某些大B细胞淋巴瘤的发展(R.Dalla-Fvera，项目3)；4)大B细胞淋巴瘤的特定亚型有独特的发病机制和合理的治疗靶点(M.Shipp，项目4)；以及5)GC B细胞淋巴瘤中非调控的凋亡和转录程序的成分可以通过一种名为碳氢化合物钉扎的新化学策略来靶向(L.Walensky，项目5)。拟议的项目在很大程度上依赖于下列核心领域的研究人员的投入和合作：DNA微阵列/生物信息学(T.Golub，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，核心C)和管理(M.Shipp/K.Rajeski，核心D)。在这个PO1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量的原发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细胞淋巴瘤的易感因素和分子基础，提高对特定实体的诊断，完善我们的预后评估和证明合理的靶点，以便进行更有效和特异的治疗干预。

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.