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）：确定TCL1（T细胞白血病-1）癌基因在B细胞发育和肿瘤中的作用的新方向由此应用突出显示。我们发现，在淋巴组织反应性生发中心（GC）中，在B淋巴细胞成熟到记忆或浆细胞中，通常会熄灭TCL1的表达。但是，使用减法杂交，我们还确定了-〜8o％的GC后辅助AIDS弥漫大型B细胞淋巴瘤患者样品中的异常，高水平的TCL1表达。这一发现使TCL1成为与Blymphomas的大型亚组相关的最普遍的致癌基因，并强烈暗示其在艾滋病 - 淋巴作用中的作用。受调节表达的模式使我们提出了一个模型，其中TCL1主要在细胞存活中起作用，并且在细胞增殖中的程度较小。我们进一步提出，下调TCL1表达的正常机制主要是表观遗传性的，并且在艾滋病中被破坏，从而导致B细胞中持续的高水平表达。如许多AIDS患者所见，否则将消除或保持静止的B细胞的保护和增殖将产生生存优势，并且长期允许累积的突变产生侵袭性的B细胞肿瘤。现在，我们的小组和其他显示TC11和AKT之间相互作用的人（蛋白激酶B）获得了对该模型的支持。 AKT充当主要促进细胞存活的必需细胞激酶。我们测试TCL1表达失调的假设可以改变正常B细胞​​稳态并促进淋巴瘤的假设很简单。我们将确定我们认为正在控制TCL1表达的表观遗传调节机制的关键特征，并研究动物模型系统中失调的生物学意义。因此，具体目的1研究调节TCL1基因活性的表观遗传机制，而特定目标II评估了我们现已建立的转基因小鼠模型中异常调节的影响。然后，特定的目标III通过检查自身抗体的发展以及通常在GCS中运行以驱动抗体多样性的机制中的误差的作用来确定TCL1如何启动B细胞转换。由于其在AKT激活级联中PTEN和其他已知肿瘤促进蛋白质的战略位置下游，这些研究还将TCL1的未来评估预示为潜在的诊断或治疗靶标分子。