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

基本信息

批准号：
10432012
负责人：
Laura Pasqualucci
金额：
$ 37.71万
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 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10432012
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 disease prognosis dosage genome-wide human disease improved in vivo insight knockout animal large cell Diffuse non-Hodgkin&apos 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

项目摘要

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

研究摘要弥漫性大B细胞淋巴瘤（DLBCL）和卵泡淋巴瘤（FL）代表两个最常见的成熟的B细胞淋巴瘤的形式占所有诊断的70％以上。两种疾病仍然是重大的临床挑战，因为大量患者人群无法实现持久的恢复常规的治疗策略。识别负责肿瘤的分子机制启动和维护，可能容易受到针对性的治疗干预措施，代表了一项研究为了提高我们治愈这些疾病的能力，必须进行。体细胞突变导致KMT2D甲基转移酶灭活是最常见的 FL中的遗传病变（占病例的80％）和DLBCL（占病例的30％），表明表观遗传学重要作用这些癌症的发病机理中的扰动（Pasqualucci等人，自然遗传学2011； Morin等，自然2011）。实际上，kMt2d体内的有条件失活导致生发中心的扩张（GC） B细胞，FL和DLBCL的正常对应物，并与Bcl2放松管制合作以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，自然医学2015； Ortega-- Molina等，《自然医学》 2015）。但是，KMT2D的GC特定删除单独的驱动肿瘤形成，表明需要其他合作事件。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％ KMT2D突变的FL和〜25％的KMT2D Mutated de Novo DLBCL。这两种改变代表了早期病变淋巴瘤（Pasqualucci等人，细胞报告2014）。此外，Crebbb乙酰是在IN中的KMT2D蛋白体内最后，这两种蛋白质的染色质结合模式显着重叠GC特异性超级 - 增强剂（Zhang等，《自然医学2015》和2017年癌症发现）。这些数据表明KMT2D 和CREBBP通过协调调节常见和特定程序在B细胞淋巴作用中合作。在这些结果的基础上，该项目的一般目标将是阐明 KMT2D和CREBBP在正常和转化的GC B细胞中，具有三个特定目的：i）确定转录程序在正常GC B细胞中由这两种蛋白质协调或组合调节，并在B细胞淋巴瘤中破坏并发灭活突变，以及CrebBP介导的作用 KMT2D功能上的乙酰化； ii）研究KMT2D/CREBBP增强子结合的作用有利于染色体易位和异常的体细胞超名； iii）检查在体内淋巴瘤启动中的KMT2D/CREBBP缺乏。我们预计结果已获得从这些研究中，通过提供对启动肿瘤转化及其特定治疗靶向的机制的新见解。 PHS 398/2590（修订版06/09）页面延续格式页面

项目成果

期刊论文数量（18）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

The genetic basis of diffuse large B-cell lymphoma.

DOI：
10.1097/moh.0b013e3283623d7f
发表时间：
2013-07
期刊：
Current opinion in hematology
影响因子：
3.2
作者：
Pasqualucci L
通讯作者：
Pasqualucci L

An oncogenic role for alternative NF-κB signaling in DLBCL revealed upon deregulated BCL6 expression.

DOI：
10.1016/j.celrep.2015.03.059
发表时间：
2015-05-05
期刊：
Cell reports
影响因子：
8.8
作者：
Zhang B;Calado DP;Wang Z;Fröhler S;Köchert K;Qian Y;Koralov SB;Schmidt-Supprian M;Sasaki Y;Unitt C;Rodig S;Chen W;Dalla-Favera R;Alt FW;Pasqualucci L;Rajewsky K
通讯作者：
Rajewsky K

Mouse Models of Germinal Center Derived B-Cell Lymphomas.