Expression und Funktion von LEF-1, einem Signaturgen des molekularen Burkitt Lymphoms, in malignen Lymphomen

Burkitt淋巴瘤是一种高度恶性、侵袭性的非霍奇金淋巴瘤。我们提出了BL的分子定义，并将LEF1确定为BL的标志基因。我们已经显示LEF1在BLS中异常表达，从而证实了我们最初的SP3假说。白血病细胞系LEF1基因表达下调与细胞周期停滞和细胞增殖抑制有关。通过基因芯片分析鉴定出新的LEF1靶基因。我们现在将解决以下问题：(1)LEF1在BL中的作用方式是什么？(Ii)导致LEF1表达异常的机制是什么？为了回答第一个问题，我们将继续研究LEF1靶基因的特征，包括LEF1结合位点的特征(ChlP-Seq)以及LEF1如何调节其靶基因以维持BLS的恶性特性(通过靶基因的过度表达/敲除)。此外，我们将在淋巴瘤细胞中系统地寻找与LEF1相互作用的蛋白质。为了回答第二个问题，我们将分析在BL和BL前体细胞中LEF1表达的调节，确定参与激活或抑制LEF1启动子的途径。为了将LEF1介导的致癌模块描述为潜在的预后或治疗标记物，将对大规模淋巴瘤基因表达谱的体外数据进行评估。

Burkitt Lymphoma (BL) is a highly malignant, aggressive Non-Hodgkin Lymphoma. We have developed a molecular definition of BL and identified LEF1 as a signature gene for BL. We have shown aberrant LEF1 expression in BLs thus approving our starting hypothesis of SP3. LEF1 knockdown in BL lines was associated with cell cycle arrest and reduced proliferation. New LEF1 target genes were identified by microarray analysis. We will now address the following questions: (1) What is the mode of action of LEF1 in BL and (ii) what is the mechanism leading to aberrant LEF1 expression? To answer the first question we will continue the characterization of LEF1 target genes including the characterization of LEF1 binding sites (ChlP-Seq) and how LEF1 regulates its target genes to sustain the malignant properties of BLs (by overexpression/knockdown of target genes). Furthermore, we will perform a systematic search for proteins interacting with LEF1 in lymphoma cells. To answer the second question we will analyse the regulation of LEF1 expression in BL and BL precursor cells identifying pathways involved in activating or inhibiting the LEF1 promoter. In order to characterise LEF1 mediated oncogenic modules as potenfial prognostic or therapeutic marker in vitro data will be evaluated on large scale lymphoma gene expression profiles.