Role of KMT2D Gene Inactivation in B cell Non Hodgkin Lymphoma

KMT2D 基因失活在 B 细胞非霍奇金淋巴瘤中的作用

• 批准号: 10198854
• 负责人: Laura Pasqualucci
• 金额: $ 38.48万
• 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 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10198854
• 关键词: Accounting; Acetylation; Acetyltransferase; Affect; Alleles; B-Cell Activation; B-Cell Lymphomas; B-Cell NonHodgkins Lymphoma; B-Lymphocyte Subsets; B-Lymphocytes; BCL2 gene; Binding; CREBBP gene; Cell Line; Cells; ChIP-seq; Chromatin; Chromosomal translocation; Chromosome abnormality; Clinical; Clonal Expansion; Comet Assay; Complex; DNA; Data; Development; Diagnosis; Diagnostic; Disease; Disease remission; EP300 gene; Engineering; Enhancers; Enzymes; Epigenetic Process; Event; Follicular Lymphoma; Gamma-H2AX; Gene Silencing; Genes; Genetic; Genetic Transcription; Goals; Human; Immunoglobulin Somatic Hypermutation; Impairment; In Vitro; Incidence; Individual; Knock-out; Knockout Mice; Lesion; Lymphoma; Lymphomagenesis; Maintenance; Malignant - descriptor; Malignant Neoplasms; Mature B-Lymphocyte; Mediating; Medicine; Methyltransferase; Molecular; Mouse Strains; Mus; Mutate; Mutation; Nature; Neoplastic Cell Transformation; Outcome Study; Pathogenesis; Patients; Pattern; Phenotype; Point Mutation; Prognosis; Protein Acetylation; Proteins; Recurrence; Regulation; Reporting; Research; Research Project Grants; Research Proposals; Role; Somatic Mutation; Structure of germinal center of lymph node; Targeted Resequencing; Testing; Therapeutic; Therapeutic Intervention; Tumor Suppressor Genes; Wild Type Mouse; base; combinatorial; conditional knockout; dosage; genome-wide; human disease; improved; in vivo; insight; knockout animal; large cell Diffuse non-Hodgkin' s lymphoma; mouse model; mutant; off-target site; p53-binding protein 1; patient population; precursor cell; programs; repaired; targeted treatment; therapeutic target; tool; transcriptome sequencing; tumor; tumor initiation; virtual

RESEARCH SUMMARY Diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL) represent the two most common forms of mature B-cell lymphoma, together accounting for over 70% of all diagnoses. Both diseases remain a significant clinical challenge, as a significant patient population does not achieve durable remissions following conventional therapeutic strategies. The identification of molecular mechanisms that are responsible for tumor initiation and maintenance, and could be vulnerable to targeted therapeutic intervention, represents a research imperative in order to advance our ability to cure these diseases. Somatic mutations leading to inactivation of the KMT2D methyltransferase emerged as the most common genetic lesion in FL (80% of cases) and DLBCL (~30% of cases), suggesting a prominent role for epigenetic perturbations in the pathogenesis of these cancers (Pasqualucci et al., Nature Genetics 2011; Morin et al., Nature 2011). Indeed, conditional inactivation of KMT2D in vivo leads to the expansion of germinal center (GC) B cells, the normal counterpart of FL and DLBCL, and cooperates with BCL2 deregulation to increase the incidence of tumors recapitulating phenotypic and genetic features of the human FL/DLBCL, thereby establishing KMT2D as a bona fide tumor suppressor gene (Zhang et al., Nature Medicine 2015; Ortega- Molina et al., Nature Medicine 2015). However, GC-specific deletion of KMT2D individually was insufficient to drive tumor formation, suggesting the requirement of additional cooperating events. We observed that KMT2D mutations are frequently associated with alterations in the CREBBP/EP300 acetyltransferases, found in 60% of KMT2D-mutated FL and ~25% of KMT2D-mutated de novo DLBCL. Both alterations represent early lesions in lymphomagensis (Pasqualucci et al, Cell Reports 2014). Moreover, CREBBP acetylates the KMT2D protein in vivo; finally, the chromatin-binding pattern of these two proteins significantly overlaps at GC-specific super- enhancers (Zhang et al., Nature Medicine 2015 and Cancer Discovery 2017). These data suggest that KMT2D and CREBBP cooperate in B cell lymphomagenesis by coordinately regulating common and specific programs. Building on these results, the general goal of this project will be to elucidate the cooperative role of KMT2D and CREBBP in normal and transformed GC B cells, with three Specific Aims: i) identify the transcriptional program coordinately or combinatorially regulated by these two proteins in normal GC B cells, and disrupted in B cell lymphomas with concurrent inactivating mutations, and the role of CREBBP-mediated acetylation on KMT2D function; ii) investigate the role of KMT2D/CREBBP enhancer binding in favoring chromosomal translocations and aberrant somatic hypermutation; and iii) examine the synergistic role of combined KMT2D/CREBBP deficiency in lymphoma initiation in vivo. We anticipate that the results obtained from these studies will impact our current understanding of the pathogenesis of these diseases, by providing new insights on the mechanisms initiating neoplastic transformation and on their specific therapeutic targeting. PHS 398/2590 (Rev. 06/09) Page Continuation Format Page

研究综述 弥漫大B细胞淋巴瘤(DLBCL)和滤泡性淋巴瘤(FL)是最常见的两种 各种类型的成熟B细胞淋巴瘤，占所有诊断的70%以上。这两种疾病仍然是 重大的临床挑战，因为大量患者在以下情况下无法实现持久缓解 传统的治疗策略。肿瘤发生的分子机制研究进展 一项研究表明，启动和维护，可能容易受到有针对性的治疗干预 为了提高我们治愈这些疾病的能力，这是当务之急。 导致KMT2D甲基转移酶失活的体细胞突变是最常见的 FL(80%的病例)和DLBCL(约30%的病例)的遗传损害，表明表观遗传学的显著作用 这些癌症发病机制中的扰动(Pasquucci等人，《自然遗传学》2011；Morin等人， 《自然》2011)。事实上，KMT2D在体内的条件失活导致生发中心(GC)的扩张 B细胞，FL和DLBCL的正常对应物，并与bcl2的解除调控合作，增加 肿瘤的发生率概括了人类FL/DLBCL的表型和遗传特征，从而 将KMT2D建立为真正的肿瘤抑制基因(Zhang等人，自然医学，2015；Ortega- Molina等人，《自然医学》，2015)。然而，GC特异性单独删除KMT2D不足以 推动肿瘤的形成，这表明需要更多的合作事件。我们观察到KMT2D 突变经常与CREBBP/EP300乙酰转移酶的改变有关，在60%的 KMT2D突变的FL和约25%的KMT2D突变的DLBCL。这两种改变都代表着早期的病变 淋巴癌(Pasquucci等人，《细胞报告2014》)。此外，CREBBP将KMT2D蛋白乙酰化 最后，这两种蛋白质的染色质结合模式在GC特异的超 增强剂(Zhang等人，《自然医学》2015和《癌症发现》2017)。这些数据表明，KMT2D CREBBP和CREBBP通过协调调节共同和特定的程序，在B细胞淋巴瘤的发生中进行合作。 在这些结果的基础上，本项目的总体目标将是阐明 KMT2D和CREBBP在正常和转化的GC B细胞中的表达，有三个特异性目的：i)鉴定 在正常GC-B细胞中，转录程序由这两种蛋白协调或联合调节， 并在同时存在失活突变的B细胞淋巴瘤中被破坏，以及CREBBP介导的作用 乙酰化对KMT2D功能的影响；ii)研究KMT2D/CREBBP增强子结合在促进 染色体易位和异常体细胞超突变；以及iii)研究 KMT2D/CREBBP联合缺陷在体内淋巴瘤发生中的作用我们预计，所取得的结果 这些研究将影响我们目前对这些疾病的发病机制的理解，通过提供 关于启动肿瘤转化的机制及其特定治疗靶点的新见解。 PHS 398/2590(06/09版)页面续格式页面