TCL1 ONCOGENE IN B LYMPHOCYTE DEVELOPMENT AND NEOPLASIA

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细胞发育和肿瘤中的作用的新方向。我们发现，在淋巴组织反应性生发中心（GC）的b淋巴细胞成熟为记忆细胞或浆细胞时，TCL1的表达通常被消灭。然而，使用减法杂交技术，我们也在-~ 80%的气相色谱衍生的艾滋病弥漫性大b细胞淋巴瘤患者样本中发现了异常的高水平TCL1表达。这一发现使得TCL1成为与b淋巴瘤亚群相关的最普遍的癌基因，并强烈暗示其在艾滋病-淋巴瘤形成中的作用。调控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，在细胞增殖中起次要作用。我们进一步提出，下调TCL1表达的正常机制主要是表观遗传的，在艾滋病中被破坏，导致b细胞中持续高水平表达。增强的b细胞的保护和增殖，否则将被消除或保持静止，将产生生存优势，长期来看，允许积累的突变产生侵略性的b细胞肿瘤，正如在许多艾滋病患者中看到的那样。我们的研究小组和其他研究人员已经证实Tc11和Akt（蛋白激酶B）之间存在相互作用，从而支持了这一模型。Akt是一种重要的细胞激酶，主要促进细胞存活。我们测试TCL1表达失调改变正常b细胞稳态并促进淋巴瘤的方法是直截了当的。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，并在动物模型系统中研究失调的生物学意义。因此，特异性目的1研究调控TCL1基因活性的表观遗传机制，特异性目的II在我们目前建立的转基因小鼠模型中评估异常调控的影响。然后，特异性目的III确定TCL1如何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错误引起的额外突变的作用来启动b细胞转化。由于其在Akt激活级联中位于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作为潜在的诊断或治疗靶分子的未来评估。

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.