Role of MLL2 Gene Inactivation in B cell Non Hodgkin Lymphoma

描述（由申请人提供）：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），占新生诊断的30-40%，也是滤泡性淋巴瘤（FL）的常见临床进展。尽管在诊断和治疗方面都取得了显著进展，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。需要做出重大努力，以确定负责疾病发展和维持的分子机制，并可以作为治疗目标。最近，我们（Pasqualucci et al., Nature 2011; Pasqualucci et al., Nature Genetics 2011）和其他人（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，分析了与DLBCL相关的基因组病变的特征，并确定了多个组蛋白/染色质重塑基因的复发性结构改变。在最近发现的遗传病变中，MLL2组蛋白H3K4三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患者表现出体细胞点突变，这种突变会去除MLL2的c端酶结构域，导致其失活（Pasqualucci等人，Nature Genetics 2011； Morin等人，Nature 2011）。在B- NHL的两种主要亚型DLBCL和FL中，这些病变的极高频率及其明显的破坏性（合在一起，占所有诊断的70%）表明MLL2在这些恶性肿瘤的发病机制中起核心作用。在这些结果的基础上，本项目的总体目标将是阐明B细胞中MLL2的正常和病理功能，具体目标如下：1)描述遗传和病理的全谱特征

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.