TCL1 ONCOGENE IN B LYMPHOCYTE DEVELOPMENT AND NEOPLASIA

描述(由申请人提供)：在确定TCL1(T细胞白血病-1)癌基因在B细胞发育和肿瘤形成中的作用方面，本申请突出了一个新的方向。我们发现，TCL1的表达通常在B淋巴细胞成熟到记忆或淋巴组织中反应性生发中心(GC)的浆细胞时消失。然而，使用消减杂交技术，我们也发现在GC衍生的艾滋病弥漫性大B细胞淋巴瘤患者样本中-80%的患者TCL1表达异常，水平高。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，并强烈暗示它在艾滋病淋巴肿大中的作用。这种受调控的表达模式使我们提出了一个模型，在该模型中，TCL1主要在细胞生存中发挥作用，其次是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学的，在艾滋病中被破坏，导致B细胞持续、高水平的表达。加强对B细胞的保护和增殖，本来会被消灭或保持静止，将产生生存优势，并从长远来看，允许累积的突变产生侵袭性B细胞肿瘤，就像许多艾滋病患者所看到的那样。我们的小组和其他显示Tc11和Akt(蛋白激酶B)之间相互作用的人现在已经获得了对这个模型的支持。AKT是一种主要促进细胞存活的必需的细胞激酶。我们对TCL1表达失调会改变正常B细胞稳态并促进淋巴瘤这一假说的检验方法很简单。我们将确定我们认为是控制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调控失调的生物学意义。因此，特异性目标1研究TCL1基因活性的表观遗传调控机制，而特异性目标II评估在我们现在建立的转基因小鼠模型中异常调控的影响。然后，特定目标III通过检查自身抗体的发展和额外突变的作用来确定TCL1是如何启动B细胞转化的，这些突变来自于GC中通常作用于推动抗体多样性的机制中的错误。由于TCL1在Akt激活级联中处于PTEN和其他已知促肿瘤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.