Molecular Targets of Germinal Center B Cell Lymphomas

描述(由申请人提供) 我们已经组建了一个由基础B细胞科学家组成的互补团队，淋巴瘤 生物学家、免疫学家、血液病理学家、基因组学和生物信息学 专家、临床研究人员和生物统计学家来描述 危重事件在发病机制和病理生理学中最为常见 成人淋巴系统恶性肿瘤和生发中心B细胞淋巴瘤， 滤泡性淋巴瘤(FL)和弥漫性大B细胞淋巴瘤(DLBCL)。虽然 近年来，这些疾病的治疗选择有所扩大，FL是 仍然无法治愈，DLBCL治愈的患者不到50%。它是 我们相信，拟议的研究将确定更多 在供资期间对这些疾病进行有效和具体的治疗。 这个新的P01应用程序基于以下假设：1)错误 免疫球蛋白基因重排与GC-B细胞的发育 淋巴瘤；2)控制细胞凋亡的基因表达异常(Bcl2) 或正常的GC发育(BCL-6)也参与了这些疾病的发病 疾病；3)独特的GC B细胞淋巴瘤的生物离散亚群 自然病史尚待确定；4)宿主免疫反应影响 GC B细胞淋巴瘤的转归。F.Alt博士和K.Rajessky博士将评估 GC B细胞淋巴瘤易位的分子机制(项目1)。 Korsmeyer博士将评估细胞凋亡作为发生中的分子靶点。 和B细胞淋巴瘤的维持(项目2)和达拉-法维拉医生将 评估bcl6在GC形成和淋巴肿大中的作用(项目3)。 M.Shipp博士将描绘GC B细胞结果的分子特征 淋巴瘤(项目4)以及L.Nadler、A.Freedman和J.Schultze博士将 分析GC B细胞淋巴瘤患者的T细胞免疫功能。支持 建议的研究包括：DNA微阵列/生物信息学(T.Golub)； 血液病理学(J.Aster)；临床试验(J.Griben)；生物统计学(D. Neuberg)和管理(M.Shipp)。

DESCRIPTION (provided by applicant) We have assembled a complementary team of basic B-cell scientists, lymphoma biologists, immunologists, hematopathologists, genomics and bioinformatics specialists, clinical investigators and biostatisticians to delineate the critical events in the pathogenesis and pathophysiology of the most common adult lymphoid malignancies and germinal center (GC) B-cell lymphomas, follicular lymphoma (FL) and diffuse large B-cell lymphomas (DLBCL). Although the treatment options for these diseases have expanded in recent years, FL is still incurable and DLBCL is cured in less than 50 percent of patients. It is our belief that the proposed studies will identify rational targets for more effective and specific treatment of these diseases in the funding period. This new P01 application is based upon the following hypothesis: 1) errors in immunoglobulin gene rearrangement predispose to the development of GC B-cell lymphomas; 2) dysregulated expression of genes controlling apoptosis (bcl-2) or normal GC development (bcl-6) also contribute to the pathogenesis of these diseases; 3) biologically-discrete subsets of GC B-cell lymphomas with unique natural histories remain to be defined; and 4) host immune responses influence outcome in GC B-cell lymphomas. Drs. F. Alt and K. Rajewsky will evaluate molecular mechanisms of translocations in GC B-cell lymphomas (Project 1). Dr. S. Korsmeyer will assess apoptosis as a molecular target in the genesis and maintenance of B-cell lymphoma (Project 2) and Dr. Dalla-Favera will evaluate the role of bcl-6 in GC formation and lymphomagenesis (Project 3). Dr. M. Shipp will delineate molecular signatures of outcome in GC B-cell lymphomas (Project 4) and Drs. L. Nadler, A. Freedman, and J. Schultze will analyze T-cell immunity in GC B-cell lymphomas. Cores which support the proposed studies include: DNA Microarray/Bioinformatics (T. Golub); Hematopathology (J. Aster); Clinical Trials (J. Gribben); Biostatistics (D. Neuberg); and Administration (M. Shipp).