Role of SMRT down-regulation in NHL transformation

描述（由申请人提供）：染色体异常的分子分析已经允许识别许多直接参与淋巴恶性肿瘤发病机制的基因。然而，在非霍奇金淋巴瘤（NHL）中，完整肿瘤表型的发展依赖于多种遗传事件的获得，包括协同“显性”癌基因的同时激活和肿瘤抑制基因功能的丧失。nhl通常呈现复杂的核型，可能妨碍完整的分析。为了克服这一困难，已经建立了许多转化的NHL细胞系。其他人和我们已经确定染色体12q24是T细胞和b细胞谱系成熟淋巴细胞恶性肿瘤的复发断点，并且最近将编码SMRT定位到12q24.3。我们观察到，在所有转化的NHL细胞系/患者中，SMRT在基因组、转录物和蛋白质水平上都发生了改变。我们建议SMRT在NHL中发挥重要作用。这表明SMRT是一种肿瘤抑制基因。为了验证这一假设，我们提出以下具体目标：1 .通过FISH、LOH和免疫组织化学对大量转化和非转化患者样本进行回顾性研究，以扩大我们对转化淋巴瘤表型和一个SMRT等位基因缺失的观察。2-研究SMRT调控SMRT缺陷型NHL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，以及不同的半胱天冬酶（及其激活）在smrt恢复驱动的细胞凋亡中的表达变化。这一目的的最终目标是确定未来的研究领域，以潜在的（新的）治疗方法来诱导smrt缺陷的NHL细胞凋亡。3-建立SMRT下调与NHL转化过程的因果关系。为此，我们将采用反义策略下调SMRT在不同正常和低等级转基因小鼠造血环境中的表达。确认SMRT在NHL转化和细胞凋亡中的作用可能有助于开发新的诊断和预后工具以及新的治疗策略。

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.