Role of MLL2 Gene Inactivation in B cell Non Hodgkin Lymphoma

MLL2 基因失活在 B 细胞非霍奇金淋巴瘤中的作用

基本信息

批准号：
8422377
负责人：
Laura Pasqualucci
金额：
$ 33.2万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-01-01 至 2017-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8422377
关键词：
Accounting Affect Algorithms Alleles B-Cell Development B-Cell NonHodgkins Lymphoma B-Lymphocytes BCL2 gene BCL6 gene Binding Biochemical Biological Biological Assay Biological Process C-terminal ChIP-seq Chromosomal translocation Clinical Deletion Mutation Development Diagnosis Diagnostic Disease Epigenetic Process Evolution Follicular Lymphoma Frequencies Gene Expression Profile Gene Mutation Gene Silencing Genes Genetic Genome Genomics Goals Histones Human Hypermethylation Immunotherapy Indolent Lesion Lymphoma Lymphomagenesis MLL2 gene Maintenance Malignant Neoplasms Mature B-Lymphocyte Messenger RNA Missense Mutation Modeling Molecular Mouse Strains Mutant Strains Mice Mutation Nature Non-Hodgkin&apos s Lymphoma Oncogenic Outcome Pathogenesis Pathologic Pathway interactions Patients Pattern Point Mutation Predisposition Proteins Proto-Oncogenes Recurrence Research Priority Research Proposals Role Single Nucleotide Polymorphism Structure of germinal center of lymph node Substrate Interaction Systems Biology Technology Therapeutic Tumor Suppressor Genes base chromatin remodeling density disorder prevention dosage enzyme substrate exome exome sequencing genome-wide improved in vivo insight large cell Diffuse non-Hodgkin&apos s lymphoma mouse model next generation novel therapeutic intervention pre-clinical programs promoter public health relevance therapeutic target tool transcriptome sequencing tumor

项目摘要

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.

描述（由申请人提供）：弥漫性大 B 细胞淋巴瘤 (DLBCL) 是非霍奇金淋巴瘤 (B-NHL) 最常见的形式，占新诊断的 30-40%，也是一种常见的疾病滤泡性淋巴瘤（FL）的临床演变。尽管诊断和治疗方面取得了显着进展，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。需要做出重大努力来确定导致疾病发展和维持的分子机制，并可以作为治疗目标。我们（Pasqualucci 等人，Nature 2011；Pasqualucci 等人，Nature Genetics 2011）和其他人（Morin 等人，Nature 2011）最近使用全基因组方法（包括下一代全外显子组测序和高密度单基因测序）进行的分析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特征，并导致了多个组蛋白/染色质重塑基因中反复出现的结构改变的鉴定。在最近发现的基因损伤中，MLL2 组蛋白 H3K4 三甲基转移酶成为最常见的靶标。总体而言，约 30% 的 DLBCL 和 89% 的 FL 患者表现出体细胞点突变，该突变去除了 MLL2 的 C 末端酶结构域，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 B-NHL 的两种主要亚型 DLBCL 和 FL 中的明显破坏性（合计占所有诊断的 70%）表明 MLL2 在这些恶性肿瘤的发病机制中发挥着核心作用。基于这些结果，该项目的总体目标是阐明 B 细胞中 MLL2 的正常和病理功能，具体目标如下： i) 表征全谱遗传和病理特征。 DLBCL 和 FL 中 MLL2 及其旁系同源物 MLL3 失活的表观遗传机制； ii) 鉴定正常 B 细胞中受 MLL2 调节的转录网络，并且在 DLBCL 中由于 MLL2 失活突变而被破坏； iii) 检查MLL2缺陷在体内淋巴瘤发生中的作用，单独或与两个额外的遗传病变配合，这两个遗传病变经常与人类肿瘤中的MLL2突变相关，即原癌基因BCL2和BCL6的染色体易位。从拟议的研究中获得的结果预计将提供 i) 重要的新信息，帮助我们了解这两种常见 B-NHL 发病机制的机制因素，ii) MLL2 驱动的淋巴瘤发生的小鼠模型，可用于临床前治疗瞄准； iii）深入了解新的治疗方法，从而为疾病预防和治疗的进一步进展奠定基础。