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.

该研究项目的一般目标是确定遗传 参与非霍奇金淋巴瘤（NHL）和TO的病变 测试他们的诊断和预后意义。以下特定 目标将被追求： 1。对诊所基形的特征和测试的表征和测试 BCl-6基因的结构改变。我们最近确定了 新型候选原子观，BCL-6，涉及染色体 影响3Q27的易位，并在高达45％的散射中重新排列 大细胞NHL，就发病率而言，最重要的NHL类型 死亡。基于这些结果，我们将：i）表征曲目 影响BCL-6的结构改变（重排/突变） NHL中的基因； ii）测试BCL-6改变作为临床的实用性 通过筛选大型NHL并将其相关的病理标记 结果具有许多相关的临床参数。 2。影响9PL3和的染色体易位分子分析 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检测到10-15％的NHL，可能更多 在分子水平上频繁。我们计划克隆参与的地区 染色体断裂点，寻找相关基因并定义 他们在NHL的改变。一旦定义了这些更改， 临床病理学相关性将如特定的目标l确定。 3。鉴定NHL中凋亡耐药性（APR）基因的鉴定。我们的 初步数据表明，NHL案例中有很大一部分包含 能够在小说中引起对凋亡的抗性的DNA序列 涉及将总肿瘤DNA转染到MYC转染的测定 大鼠1细胞和血清剥夺凋亡的诱导。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其频率 淋巴恶性肿瘤。最终，我们将测试这些效用 作为临床病理标记的变化如特定目标1。 总结这些研究的结果应进一步 了解NHL的发病机理，并提供标记以改善 该异质组的诊断，预后和临床监测 肿瘤。