TCL1 Oncogene in B Lymphocyte Development and Neoplasia

描述(申请人提供)：大多数淋巴系统恶性肿瘤由生发中心(GC)经历的B细胞转化而来。在最初的资助期间，我们发现TCL1原癌基因在三种主要GC B细胞淋巴瘤类别的样本中异常表达。我们最初的特定目标解决了TCL1异常表达在GC B细胞转化中起积极作用而不是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转录调控的第一个分析，(2)发展了与人类GC B细胞淋巴瘤非常相似的肿瘤的TCL1转基因模型，以及(3)TCL1启动的GC B细胞恶性肿瘤的关键遗传和表观遗传学变化概要。在这次竞争性更新中，我们以这些成功为基础，提出了三个新的具体目标，重点是调节GC B细胞中TCL1的详细机制(S)和GC B细胞淋巴瘤中TCL1的异常调节。基于TCL1在B淋巴癌发生中的启动作用，我们预测纠正异常表达的TCL1将阻止恶变。进一步支持TCL1在GC B细胞转化中的作用是观察到60%到100%的滤泡性(FL)、Burkitt(BL)和弥漫性大B细胞(DLBCL)淋巴瘤TCL1水平异常。最近的工作揭示了强健的、异常的TCL1表达在人类BL的发病机制和分子诊断中的作用。我们还表明，TCL1特异性地增强了PI3K和PKC信号通路，这些信号通路控制着B细胞的增殖和存活。因此，特定的目标1确定了转化的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。特定目的2确定控制原代人类B细胞中特定阶段TCL1表达的正常调控程序，以与TCL1失调的机制进行比较。特异性目标3使用AIMS 1和2中确定的TCL1转录激活和抑制物连接通路的操纵来评估TCL1改变的GC B细胞和GC B细胞淋巴瘤对增殖和生存的影响。我们的研究结合了IRB批准和表征的患者样本和分离的原始B细胞，通过控制TCL1原癌基因的表达为潜在的治疗干预提供临床相关的见解，以了解GC B细胞淋巴瘤的发病机制。

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.