Role of acetyltransferase gene inactivation in follicular lymphoma pathogenesis

描述（由申请人提供）：滤泡性淋巴瘤（滤泡性淋巴瘤）是第二常见的b细胞非霍奇金淋巴瘤（B-NHL），约占新生诊断的30% （Swerdlow et al., 2008）。尽管其惰性性质和新治疗方案的发展取得了进展，但FL仍然无法治愈，这强调了确定导致疾病发展和可靶向治疗的分子机制的必要性。因此，确定新的癌基因和肿瘤抑制因子，并确定其正常细胞功能和在淋巴瘤发生中的作用，仍然是一项重要的研究，以开发有针对性的、高度特异性的治疗方法。通过下一代全外显子组测序分析和高密度单核苷酸多态性（SNP）阵列分析，我们发现超过40%的FL病例与CREBBP （CBP）和EP300 （p300）失活的结构改变有关，这两种高度相关的组蛋白和非组蛋白乙酰转移酶（HATs）在多种信号通路中起转录共激活剂的作用。我们已经证明，CBP/p300失活导致乙酰化介导的BCL6癌蛋白失活和p53肿瘤抑制因子激活中的特异性缺陷，因此提出了这些病变可能促进细胞转化的一种可能机制（Pasqualucci等人，Nature, in press）。基于这些结果，本项目的总体目标是阐明CBP和p300在FL发病机制中的作用，并为其治疗靶向建立临床前模型。将实现以下具体目标：目标1。确定影响FL患者CBP/p300的全谱遗传和表观遗传病变。通过鉴定受p300调控并受其失活影响的基因，确定FL中p300失活的后果。目标3。通过构建B细胞中CBP或p300失活联合BCL2的解除，从而模拟人类FL的小鼠，阐明CBP和p300失活在FL发病中的作用

DESCRIPTION (provided by applicant): Follicular Lymphoma (FL) represents the second most common form of B-cell non-Hodgkin Lymphoma (B-NHL), accounting for ~30% of the de-novo diagnoses (Swerdlow et al., 2008). Despite its indolent nature and progress in the development of new therapeutic regimens FL remains incurable, underscoring the need to identify molecular mechanisms that are responsible for disease development and that can be targeted therapeutically. Thus, identifying new oncogenes and tumor suppressors and defining their normal cellular functions and role in lymphomagenesis remains a major research imperative in order to develop targeted, highly specific therapies. Using next-generation whole-exome sequencing analysis and high-density single nucleotide polymorphism (SNP) array analysis we have shown that over 40% of FL cases are associated with structural alterations inactivating CREBBP (CBP) and EP300 (p300), two highly related histone and non-histone acetyltransferases (HATs) that act as transcriptional co-activators in multiple signaling pathways. We have demonstrated that CBP/p300 inactivation leads to specific defects in the acetylation-mediated inactivation of the BCL6 onco-protein and activation of the p53 tumor suppressor, therefore suggesting one possible mechanism by which these lesions may contribute to cell transformation (Pasqualucci et al., Nature, in press). Based on these results, the general objective of this project is to elucidate the role of CBP and p300 in FL pathogenesis and to establish pre-clinical models for their therapeutic targeting. The following Specific Aims will be pursued: Aim 1. Identify the full spectrum of genetic and epigenetic lesions affecting CBP/p300 in FL. Aim 2. Identify consequences of p300 inactivation in FL by identifying genes regulated by p300 and affected by its inactivation. Aim 3. Elucidate the role of CBP and p300 inactivation in FL pathogenesis in vivo by constructing mice in which CBP or p300 inactivation in B cells is combined deregulation of BCL2, thus mimicking human FL