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

• 批准号: 8600247
• 负责人: Laura Pasqualucci
• 金额: $ 32.2万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 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/8600247
• 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' 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' s lymphoma; mouse model; next generation; novel therapeutic intervention; pre-clinical; programs; promoter; public health relevance; therapeutic target; tool; transcriptome sequencing; tumor

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(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)，占新诊断的30%-40%，也是滤泡性淋巴瘤(FL)的一种频繁的临床演变。尽管在诊断和治疗方面都取得了显著的进步，但DLBCL仍然是一个巨大的临床挑战，因为近50%的患者无法通过现有的治疗方法治愈。需要作出重大努力，以确定负责疾病发展和维持的分子机制，并可作为治疗靶点。最近我们(Pasqualucci等人，自然2011；Pasqualucci等人，自然遗传学2011)和其他人(Morin等人，自然2011)使用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在内的全基因组方法进行的最新分析表征了与DLBCL相关的基因组损伤的格局，并导致在多个组蛋白/染色体重塑基因中发现了反复发生的结构改变。在最近发现的遗传损伤中，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，这些突变移除了MLL2的C末端酶切域，导致其失活(PasQuucci等人，自然遗传学2011年；Morin等人，自然2011年)。这些病变的发生率极高，在DLBCL和FL中具有明显的破坏性，这两种主要的B-NHL亚型(合并起来，高达所有诊断的70%)表明MLL2在这些恶性肿瘤的发病机制中发挥着核心作用。在这些结果的基础上，这个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：i)表征全谱的遗传和 MLL2缺乏在DLBCL和FL中影响MLL2及其伴生区MLL3的表观遗传学机制；ii)确定在正常B细胞中受MLL2调控的转录网络，并由于MLL2失活突变而在DLBCL中被破坏；iii)单独或与另外两个被发现与人类肿瘤中的MLL2突变有关的另外两种遗传损伤(即原癌基因BCL2和BCL6的染色体易位)一起在体内检测MLL2缺陷在淋巴癌发生中的作用。这些拟议研究的结果有望为我们理解这两种常见的B-NHL的发病机制提供重要的新信息；ii)可用于临床前治疗靶点的MLL2驱动的淋巴肿大小鼠模型；iii)对新的治疗方法的见解，从而为疾病预防和治疗的进一步进展奠定基础。