TCL1 Oncogene in B Lymphocyte Development and Neoplasia

描述（由申请方提供）：大多数淋巴恶性肿瘤是由生殖中心（GC）经历的B细胞转化引起的。在最初的资助期间，我们发现，TCL 1原癌基因异常表达的样本中的三个主要GC B细胞淋巴瘤类别。我们最初的特定目的解决了主要假设，即异常的TCL 1表达在转化GC B细胞中具有主动而非被动作用。我们成功地完成了这些目标，提供了（1）第一次分析的TCL 1转录控制，（2）TCL 1转基因模型，发展肿瘤非常类似于人类GC B细胞淋巴瘤，和（3）的纲要关键遗传和表观遗传变化的TCL 1启动的GC B细胞恶性肿瘤。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TCL 1和GC B细胞淋巴瘤中失调TCL 1的详细机制。基于TCL 1在B淋巴瘤发生中的起始作用，我们预测纠正TCL 1表达失调将阻止恶性变性。进一步支持TCL 1在GC B细胞转化中的致病作用的是观察到60 - 100%的滤泡（FL）、伯基特（BL）和弥漫性大B细胞（DLBCL）淋巴瘤显示出失调的TCL 1水平。最近的工作已经揭示了强大的，异常的TCL 1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，TCL 1特异性增强已知控制B细胞增殖和存活的PI 3 K和PKC信号通路。因此，特异性目的1确定了转化的GC B细胞系中促进异常TCL 1表达的调节机制，作为控制体内失调表达的类似机制的合理代表。具体目标2鉴定了控制原代人B细胞中阶段特异性TCL 1表达的正常调节程序，用于与TCL 1失调机制进行比较。特定目的3使用目的1和2中鉴定的TCL 1转录激活因子和阻遏物连接途径的操作，以评估对TCL 1改变的GC B细胞和GC B细胞淋巴瘤的增殖和存活的影响。我们的研究包括IRB批准和表征的患者样本和分离的原代B细胞，通过控制TCL 1原癌基因表达以进行潜在的治疗干预，为GC B细胞淋巴瘤的发病机制提供临床相关见解。

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.