Role of SMRT down-regulation in NHL transformation

SMRT 下调在 NHL 转化中的作用

• 批准号: 6728245
• 负责人: LIONEL J COIGNET
• 金额: $ 30.26万
• 依托单位: ROSWELL PARK CANCER INSTITUTE CORP
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-04-01 至 2007-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6728245
• 关键词: apoptosis; cell line; chromosomes; cysteine endopeptidases; flow cytometry; fluorescent in situ hybridization; gene expression; genetically modified animals; hormone receptor; human tissue; immunocytochemistry; laboratory mouse; nonHodgkin' s lymphoma; nuclear receptors; oncogenes; polymerase chain reaction; tumor suppressor genes; western blottings

DESCRIPTION (provided by applicant): Molecular analysis of chromosomal abnormalities has allowed the identification of many genes directly involved in the pathogenesis of lymphoid malignancies. However, in non-Hodgkin's lymphoma (NHL), the development of the full neoplastic phenotype depends on the acquisition of multiple genetic events including concurrent activation of synergistic "dominant" oncogenes and loss of tumor suppressor gene functions. NHLs often present complex karyotypes that may prevent complete analysis. To overcome this difficulty, many transformed NHL cell lines have been established. Others and we have identified chromosome 12q24 as a recurrent breakpoint in mature lymphoid malignancies of both T- and B-cell lineage and have recently mapped the gone encoding SMRT to 12q24.3. We observed that SMRT is altered in all transformed NHL cell lines/patients tested at the genomic, transcript and protein levels. We propose that SMRT plays an important role in NHL. This implies that SMRT acts as a tumor suppressor gene. To test this hypothesis, we propose the following Specific Aims: 1-To perform a retrospective study of a large series of transformed and non-transformed patient samples by FISH, LOH and immunohistochemistry, to expand upon our observation of transformed lymphoma phenotype and deletion of one SMRT allele. 2- To study the mechanisms by which SMRT regulates apoptosis and cell survival in SMRT-deficient NHL cells. For this purpose, we will study variation of expression of a set of genes involved in cell survival and of the different caspases (and their activation) upon SMRT-restoration-driven apoptosis. The ultimate goal of this aim is to identify future investigative area for potential (new) therapeutic approaches to induce apoptosis in SMRT-deficient NHL cells. 3- To establish a cause: effect relationship between SMRT down-regulation and the NHL transformation process. For this purpose, we will use an antisense strategy to down-regulate SMRT in different normal and low-grade transgenic mice hematopoietic environment. Confirmation of the role of SMRT in NHL transformation and in apoptosis could potentially allow development of new diagnostic and prognostic tools as well as new therapeutic strategies.

描述（由申请人提供）：染色体异常的分子分析允许鉴定许多直接参与淋巴恶性肿瘤发病机理的基因。然而，在非霍奇金淋巴瘤（NHL）中，完整的肿瘤表型的发展取决于获取多个遗传事件，包括同时激活协同“显性”癌基因和肿瘤抑制基因功能的丧失。 NHL通常呈现复杂的核型，以阻止完全分析。为了克服这一困难，已经建立了许多转化的NHL细胞系。 其他人，我们已经将12q24染色体确定为T和B细胞谱系成熟的淋巴恶性肿瘤中的复发断裂点，最近将GOND编码的SMRT映射到12q24.3。我们观察到，在基因组，转录和蛋白质水平测试的所有转化的NHL细胞系/患者中，SMRT都会改变。我们建议SMRT在NHL中起重要作用。这意味着SMRT充当肿瘤抑制基因。为了检验这一假设，我们提出了以下具体目的：1对通过鱼类，LOH和免疫组织化学进行一系列转化和非转化的患者样品进行回顾性研究，以扩展我们对一个SMRT等位基因转化的淋巴瘤表型和缺失的观察。 2-研究SMRT调节SMRT缺陷型NHL细胞中细胞凋亡和细胞存活的机制。为此，我们将研究一组参与细胞存活的基因的表达变化以及在SMRT恢复驱动的细胞凋亡时的不同caspase（及其激活）的变化。该目标的最终目标是确定未来的研究领域（新的）治疗方法，以诱导SMRT缺陷型NHL细胞中凋亡。 3-建立原因：SMRT下调与NHL转换过程之间的效果关系。为此，我们将使用反义策略在不同的正常和低度转基因小鼠造血环境中下调SMRT。确认SMRT在NHL转化和细胞凋亡中的作用可能有可能允许开发新的诊断和预后工具以及新的治疗策略。