MOLECULAR PATHOLOGY OF HUMAN LYMPOID MALIGNANCIES

人类淋巴恶性肿瘤的分子病理学

• 批准号: 2091351
• 负责人: Riccardo Dalla-Favera
• 金额: $ 30.95万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 1989
• 资助国家: 美国
• 起止时间: 1989-07-15 至 1999-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2091351
• 关键词: apoptosis; chromosome translocation; cytogenetics; gene mutation; genetic markers; human tissue; molecular oncology; molecular pathology; neoplasm /cancer diagnosis; neoplasm /cancer genetics; nonHodgkin's lymphoma; nucleic acid structure; oligonucleotides; prognosis; protooncogene; tissue /cell culture

The general objective of this research project is to identify genetic lesions involved in the pathogenesis of non-Hodgkin lymphoma (NHL) and to test their diagnostic and prognostic significance. The following specific aims will be pursued: 1. Characterization and testing of the clinico-prognostic significance of structural alterations of the BCL-6 gene. We have recently identified a novel candidate protooncogene, BCL-6, which is involved in chromosomal translocations affecting 3q27 and is rearranged in up to 45% of diffuse large cell NHL, the most significant NHL type in terms of morbidity and mortality. Based on these results we will: i) Characterize the repertoire of structural alterations (rearrangements/mutations) affecting the BCL-6 gene in NHL; ii) Test the utility of BCL-6 alterations as clinico- pathologic markers by screening a large panel of NHL and correlating the results with a number of relevant clinical parameters. 2. Molecular analysis of chromosomal translocations affecting 9pl3 and l0q24 in NHL. Alterations involving chromosomal regions 9pl3 and 10q24 are detectable in 10-15% of NHL at the cytogenetic level and may be more frequent at the molecular level. We plan to clone the regions involved in the chromosomal breakpoints, search for the involved genes and define their alterations in NHL. Once these alterations will be defined, their clinico-pathologic relevance will be determined as in Specific Aim l. 3. Identification of altered apoptosis-resistance (APR) genes in NHL. Our preliminary data indicate that a significant fraction of NHL cases contain DNA sequences which are able to cause resistance to apoptosis in a novel assay involving the transfection of total tumor DNA into MYC-transfected Rat-1 cells and induction of apoptosis by serum deprivation. We plan to characterize these sequences, identify the putative APR genes, identify the nature of the activating mutations and determine their frequency in lymphoid malignancies. Eventually, we will test the utility of these alterations as clinico-pathologic markers as in Specific Aim 1. Taken together the results of these studies should lead to further understanding of the pathogenesis of NHL and provide markers for improved diagnosis, prognosis and clinical monitoring of this heterogeneous group of neoplasms.

该研究项目的总体目标是确定遗传 涉及非霍奇金淋巴瘤（NHL）发病机制的病变 测试其诊断和预后意义。具体如下 将追求的目标是： 1. 临床预后意义的表征和测试 BCL-6 基因的结构改变。我们最近确定了一个 新的候选原癌基因 BCL-6，参与染色体 易位影响 3q27，并在高达 45% 的弥漫性区域中重新排列 大细胞 NHL，就发病率和发病率而言最重要的 NHL 类型 死亡。根据这些结果，我们将： i) 描述曲目的特征 影响 BCL-6 的结构改变（重排/突变） NHL 基因； ii) 测试 BCL-6 改变作为临床的效用 通过筛查大量 NHL 并将其与病理标志物相关联 结果与许多相关的临床参数。 2. 影响 9pl3 和 9pl3 的染色体易位的分子分析 NHL 中的 l0q24。涉及染色体区域 9pl3 和 10q24 的改变是 在细胞遗传学水平上可在 10-15% 的 NHL 中检测到，并且可能更多 常见于分子水平。我们计划克隆涉及的区域 染色体断点，搜索相关基因并定义 他们在 NHL 中的改变。一旦定义了这些变更，它们的 临床病理相关性将按照具体目标 l 确定。 3. NHL 中改变的凋亡抗性（APR）基因的鉴定。我们的 初步数据表明，很大一部分 NHL 病例包含 能够在新型中引起细胞凋亡抵抗的DNA序列 涉及将总肿瘤 DNA 转染至 MYC 转染细胞的测定 Rat-1 细胞和血清剥夺诱导细胞凋亡。我们计划 表征这些序列，识别推定的 APR 基因，识别 激活突变的性质并确定它们的频率 淋巴系统恶性肿瘤。最终，我们将测试这些的实用性 改变作为临床病理标志物，如具体目标 1 中所示。 综合起来，这些研究的结果应该会导致进一步的 了解 NHL 的发病机制并为改善 NHL 的发病机制提供标志物 该异质群体的诊断、预后和临床监测 肿瘤。