Role of MLL2 Gene Inactivation in B cell Non Hodgkin Lymphoma

描述（由申请方提供）：弥漫性大B细胞淋巴瘤（DLBCL）是最常见的非霍奇金淋巴瘤（B- NHL），占新发诊断的30-40%，也是滤泡性淋巴瘤（FL）的常见临床演变。尽管在诊断和治疗方面取得了显着进展，但DLBCL仍然是一个重大的临床挑战，因为近50%的患者无法通过现有的治疗方法治愈。主要的努力是需要对识别的分子机制，负责疾病的发展和维护，并可以治疗靶向。我们最近的分析（Pasqualucci等人，Nature 2011; Pasqualucci等人，Nature Genetics 2011）等（Morin et al.，Nature 2011）使用全基因组方法，包括下一代全外显子组测序和高密度单核苷酸多态性阵列分析，已经表征了与DLBCL相关的基因组病变的景观，并且已经导致鉴定了多个组蛋白/染色质重塑基因中的复发性结构改变。在最近发现的遗传病变中，MLL 2组蛋白H3 K4三甲基转移酶成为最常见的靶点。总体而言，约30%的DLBCL和89%的FL患者显示去除MLL 2的C末端酶结构域的体细胞点突变，导致其失活（Pasqualucci等人，Nature Genetics 2011; Morin等人，Nature 2011）。这些病变的极高频率及其在DLBCL和FL（B- NHL的两种主要亚型）中的明显破坏性性质（组合，高达所有诊断的70%）表明MLL 2在这些恶性肿瘤的发病机制中的中心作用。 在这些结果的基础上，本项目的总体目标将是阐明MLL 2在B细胞中的正常和病理功能，具有以下具体目的：i）表征MLL 2的全部遗传谱， ii）鉴定在正常B细胞中由MLL 2调节并且在DLBCL中由于MLL 2失活突变而被破坏的转录网络; iii）检查MLL 2缺陷在体内淋巴瘤发生中的作用，单独或与两种另外的遗传病变联合使用，所述另外的遗传病变被发现与人类肿瘤中的MLL 2突变，即原癌基因BCL 2和BCL 6的染色体易位，复发相关。 从所提出的研究中获得的结果预期提供i）重要的新信息，有助于我们理解这两种常见B-NHL的发病机制的机制因素，ii）MLL 2驱动的淋巴瘤发生的小鼠模型，其可用于临床前治疗靶向; iii）对新型治疗方法的见解，从而为疾病预防和治疗的进一步进展奠定基础。

DESCRIPTION (provided by applicant): Diffuse large B-cell lymphoma (DLBCL) represents the most common form of non-Hodgkin lymphoma (B- NHL), accounting for 30-40% of the de-novo diagnoses and also arising as a frequent clinical evolution of follicular lymphoma (FL). Despite remarkable advances in both diagnosis and treatment, DLBCL remains a significant clinical challenge, as nearly 50% of patients are not cured by available therapeutic approaches. Major efforts are needed toward the identification of the molecular mechanisms that are responsible for disease development and maintenance, and can be therapeutically targeted. Recent analysis by us (Pasqualucci et al., Nature 2011; Pasqualucci et al., Nature Genetics 2011) and others (Morin et al., Nature 2011) using genome-wide approaches including next generation whole-exome sequencing and high-density single nucleotide polymorphism array analysis have characterized the landscape of genomic lesions that are associated with DLBCL, and have led to the identification of recurrent structural alterations in multiple histone/chromati remodeling genes. Among the recently discovered genetic lesions, the MLL2 histone H3K4 trimethyltransferase emerged as the most common target. Overall, ~30% of DLBCL and 89% of FL patients display somatic point mutations that remove the C-terminal enzymatic domain of MLL2, leading to its inactivation (Pasqualucci et al., Nature Genetics 2011; Morin et al., Nature 2011). The extremely high frequency of these lesions and their clearly disruptive nature in DLBCL and FL, the two major subtypes of B- NHL (combined, up to 70% of all diagnoses) indicate a central role for MLL2 in the pathogenesis of these malignancies. Building on these results, the general goal of this project will be to elucidate the normal and pathologic function o MLL2 in B cells, with the following Specific Aims: i) characterize the full spectrum of genetic and epigenetic mechanisms of inactivation affecting MLL2 and its paralogue MLL3 in DLBCL and FL; ii) identify the transcriptional network that is regulated by MLL2 in normal B cells, and is disrupted in DLBCL as a consequence of MLL2 inactivating mutations; iii) examine the role of MLL2 deficiency in lymphomagenesis in vivo, alone or in cooperation with two additional genetic lesions that are found recurrently associated with MLL2 mutations in the human tumors, namely chromosomal translocations of the proto-oncogenes BCL2 and BCL6. The results obtained from the proposed studies are expected to provide i) significant new information toward our understanding of the mechanistic factors that underlie the pathogenesis of these two common B- NHLs, ii) mouse models of MLL2-driven lymphomagenesis that may serve for preclinical therapeutic targeting; iii) insights into novel therapeutic approaches, thus paving the basis for further advancements in disease prevention and treatment.