TCL1 Oncogene in B Lymphocyte Development and Neoplasia

描述（由申请人提供）：大多数淋巴细胞恶性肿瘤是由生发中心（GC）经历的B细胞转化引起的。在最初的资助期内，我们发现TCL1原癌基因在三种主要GC B细胞淋巴瘤类型的样本中异常表达。我们的原始特异性目标解决了TCL1异常表达在转化GC B细胞中具有主动而非被动作用的主要假设。我们成功地完成了这些目标，提供了(1)TCL1转录控制的首次分析，(2)TCL1转基因模型发展出与人类GC B细胞淋巴瘤非常相似的肿瘤，以及(3)TCL1引发的GC B细胞恶性肿瘤的关键遗传和表观遗传变化的概要。在这一竞争性更新中，我们在这些成功的基础上建立了三个新的特异性目标，重点关注GC B细胞中调节TCL1和GC B细胞淋巴瘤中TCL1失调的详细机制。基于TCL1在B淋巴瘤形成中的启动作用，我们预测纠正失调的TCL1表达将阻碍恶性变性。进一步支持TCL1在GC B细胞转化中的致病作用的观察是，60%至100%的滤泡性（FL）、伯基特（BL）和弥漫性大B细胞（DLBCL）淋巴瘤显示TCL1水平失调。最近的研究揭示了TCL1在人类BL发病机制和分子诊断中的作用。我们还发现TCL1特异性地增强了已知控制B细胞增殖和存活的PI3K和PKC信号通路。因此，Specific Aim 1确定了转化GC - B细胞系中促进TCL1异常表达的调节机制，作为体内控制异常表达的类似机制的合理代表。Specific Aim 2鉴定了控制原代人B细胞阶段特异性TCL1表达的正常调控程序，并与TCL1失调的机制进行了比较。特异性目标3使用目标1和目标2中发现的TCL1转录激活因子和抑制因子连接途径的操作来评估TCL1改变的GC B细胞和GC B细胞淋巴瘤的增殖和存活的影响。我们的研究纳入了经irb批准和鉴定的患者样本和分离的原代B细胞，通过控制TCL1原癌基因表达为潜在的治疗干预提供有关GC B细胞淋巴瘤发病机制的临床相关见解。

DESCRIPTION (provided by applicant): Most lymphoid malignancies arise by transformation of germinal center (GC) experienced B cells. In the initial funded period we showed that the TCL1 protooncogene was abnormally expressed in samples from the three major GC B cell lymphoma categories. Our Original Specific Aims addressed the main hypothesis that abnormal TCL1 expression had an active rather than a passive role in transforming GC B cells. We successfully completed these Aims by providing (1) a first analysis of TCL1 transcriptional control, (2) a TCL1 transgenic model that developed tumors strongly resembling human GC B cell lymphomas, and (3) a compendium of key genetic and epigenetic changes in TCL1-initiated GC B cell malignancies. In this competitive renewal, we build on these successes with three New Specific Aims that focus on the detailed mechanism(s) regulating TCL1 in GC B cells and dysregulating TCL1 in GC B cell lymphomas. Based on an initiating role for TCL1 in B lymphomagenesis, we predict that correcting dysregulated TCL1 expression will impede malignant degeneration. Further supporting a causative role for TCL1 in GC B cell transformation is the observation that 60 to 100% of follicular (FL), Burkitt (BL) and diffuse large B cell (DLBCL) lymphomas show dysregulated TCL1 levels. Recent work has revealed a role for robust, aberrant TCL1 expression in the pathogenesis and molecular diagnosis of human BL. We have also shown that TCL1 specifically augments both PI3K and PKC signaling pathways known to control B cell proliferation and survival. Therefore, Specific Aim 1 determines the regulatory mechanisms in transformed GC B cell lines that promote abnormal TCL1 expression as reasonable representations of similar mechanisms that control dysregulated expression in vivo. Specific Aim 2 identifies the normal regulatory program that controls stage- specific TCL1 expression in primary human B cells for comparisons with mechanisms of TCL1 dysregulation. Specific Aim 3 uses manipulations of the TCL1 transcriptional activator and repressor linked pathways identified in Aims 1 and 2 to assess the effects on proliferation and survival of TCL1-altered GC B cells and GC B cell lymphomas. Our studies incorporate IRB-approved and characterized patient samples and isolated primary B cells to provide clinically relevant insights into the pathogenesis of GC B cell lymphomas by controlling TCL1 protooncogene expression for potential therapeutic interventions.