TCL1 ONCOGENE IN B LYMPHOCYTE DEVELOPMENT AND NEOPLASIA

B 淋巴细胞发育和肿瘤中的 TCL1 癌基因

• 批准号: 6507940
• 负责人: MICHAEL A TEITELL
• 金额: $ 26.78万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-08-05 至 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6507940
• 关键词: AIDS related neoplasm /cancer; B cell lymphoma; B lymphocyte; antibody formation; cell differentiation; cell line; disease /disorder model; gene expression; genetic regulation; genetic transcription; genetically modified animals; human tissue; laboratory mouse; neoplasm /cancer genetics; neoplastic transformation; oncogenes

DESCRIPTION (provided by the applicant): A new direction in determining the role of the TCL1 (T cell leukemia-1) oncogene in B-cell development and neoplasia is highlighted by this application. We found that TCL1 expression is normally extinguished during B-lymphocyte maturation to memory or plasma cells in reactive germinal centers (GC) of lymphoid tissues. However, using subtractive hybridization, we also identified aberrant, high level TCL1 expression in -~8O% of post-GC-derived AIDS diffuse large B-cell lymphoma patient samples. This discovery makes TCL1 the most prevalent oncogene associated with this large subgroup of B-lymphomas and strongly implicates its role in AIDS-lymphomagenesis. The pattern of regulated expression led us to propose a model in which TCL1 primarily functions in cell survival and to a lesser extent in cell proliferation. We further propose that the normal mechanisms that down-regulate TCL1 expression are mainly epigenetic and are disrupted in AIDS, resulting in sustained, high level expression in B-cells. Increased protection and proliferation of B-cells that otherwise would be eliminated or kept quiescent would yield a survival advantage and, over the long-term, allow accumulated mutations to yield aggressive B-cell tumors, as seen in many AIDS patients. Support for this model has now been obtained by our group and by others who have shown an interaction between Tc11 and Akt (protein kinase B). Akt functions as an essential cellular kinase that mainly promotes cell survival. Our approach for testing the hypothesis that dysregulated TCL1 expression alters normal B-cell homeostasis and promotes lymphomas is straightforward. We will determine key features of the epigenetic regulatory mechanisms we believe are controlling TCL1 expression and investigate the biological significance of dysregulation in an animal model system. Accordingly, specific aim 1 studies the epigenetic mechanisms regulating TCL1 gene activity while specific aim II assesses the impact of abnormal regulation in our now established transgenic mouse model. Then, specific aim III determines how TCL1 initiates B-cell transformation by examining the development of autoantibodies and the role of additional mutations from errors in the mechanisms that normally operate in GCs to drive antibody diversity. Because of its strategic position down-stream of PTEN and other known tumor promoting proteins in the Akt activation cascade, these studies also presage future evaluations of TCL1 as a potential diagnostic or therapeutic target molecule.

描述（由申请人提供）：本申请强调了确定 TCL1（T 细胞白血病-1）癌基因在 B 细胞发育和瘤形成中的作用的新方向。我们发现，在淋巴组织反应性生发中心 (GC) 中，B 淋巴细胞成熟为记忆细胞或浆细胞期间，TCL1 表达通常会消失。然而，使用消减杂交，我们还在 GC 后衍生的 AIDS 弥漫性大 B 细胞淋巴瘤患者样本中鉴定出异常的高水平 TCL1 表达。这一发现使 TCL1 成为与这一大类 B 淋巴瘤相关的最常见的癌基因，并强烈暗示其在艾滋病淋巴瘤发生中的作用。调节表达的模式使我们提出了一个模型，其中 TCL1 主要在细胞存活中发挥作用，在较小程度上在细胞增殖中发挥作用。我们进一步提出，下调 TCL1 表达的正常机制主要是表观遗传，并且在 AIDS 中被破坏，导致 B 细胞持续高水平表达。增强 B 细胞的保护和增殖，否则这些 B 细胞将被消除或保持静止状态，从而产生生存优势，并且从长远来看，积累的突变会产生侵袭性 B 细胞肿瘤，正如在许多艾滋病患者中所看到的那样。我们的团队和其他人已经证明了 Tc11 和 Akt（蛋白激酶 B）之间的相互作用，现在已经获得了对该模型的支持。 Akt 作为一种重要的细胞激酶，主要促进细胞存活。我们检验 TCL1 表达失调会改变正常 B 细胞稳态并促进淋巴瘤这一假设的方法很简单。我们将确定我们认为控制 TCL1 表达的表观遗传调控机制的关键特征，并研究动物模型系统中失调的生物学意义。因此，具体目标 1 研究调节 TCL1 基因活性的表观遗传机制，而具体目标 II 评估异常调节对我们现已建立的转基因小鼠模型的影响。然后，具体目标 III 通过检查自身抗体的发展以及 GC 中正常运作的机制错误产生的额外突变的作用来确定 TCL1 如何启动 B 细胞转化，以驱动抗体多样性。由于其在 Akt 激活级联中 PTEN 和其他已知肿瘤促进蛋白下游的战略地位，这些研究也预示着 TCL1 作为潜在诊断或治疗靶分子的未来评估。