The Tumor Suppressor Function of Dnmt3a in Chronic Lymphocytic Leukemia

Dnmt3a在慢性淋巴细胞白血病中的抑癌作用

基本信息

批准号：
9233057
负责人：
Rene Opavsky
金额：
$ 34.88万
依托单位：
UNIVERSITY OF FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-12-01 至 2020-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9233057
关键词：
Accounting Address Adult Affect Apoptosis B lymphoid malignancy B-Cell Leukemia B-Lymphocytes Biological Biology CD19 gene Carcinogens Cell Line Cell surface Cells Chronic Lymphocytic Leukemia Code Cytosine DNA DNA Modification Methylases DNMT3B gene DNMT3a Data Databases Development Diagnosis Disease Disease Progression Down-Regulation Due Process Epigenetic Process Event Frequencies Gene Expression Profiling Gene Targeting Genes Genetic Genetic Transcription Genome Genomic DNA Hematopoietic Hematopoietic System Hematopoietic stem cells Human Human Development In Vitro Individual Injectable Injection of therapeutic agent Libraries Link Maintenance Malignant Neoplasms Mature B-Lymphocyte Methylation Methyltransferase Molecular Molecular Profiling Mus Mutation Myelogenous Oncogenes Oncogenic PTPRC gene Pathogenesis Pharmaceutical Preparations Phenotype Physiological Processes Prevention Property Proteins Radiation Role Sampling Spleen Surface T-Lymphocyte Testing Transcription Repressor/Corepressor Transcriptional Regulation Tumor Suppressor Proteins United States Up-Regulation Virus adult leukemia bisulfite sequencing experimental study gene function genome-wide genome-wide analysis hematopoietic tissue in vivo insight knock-down leukemia metaplastic cell transformation mouse development overexpression promoter public health relevance reconstitution self-renewal targeted treatment tumor

项目摘要

DESCRIPTION (provided by applicant): Chronic lymphocytic leukemia (CLL) is a heterogeneous B-cell malignancy with no association with carcinogens, viruses, radiation or underlying genetic defect identified to date. The disease is characterized by an accumulation of mature B-cells in hematopoietic tissues and it is incurable at present. Cytosine methylation of mammalian genomic DNA is critical for normal physiological processes due to its contribution to transcriptional regulation of large sets of genes. Recent genome-wide analysis of human CLL samples revealed a global hypomethylation of the coding portion of the genome, suggesting involvement of DNA methyltransferases (Dnmts) in the pathogenesis of the disease. To induce hypomethylation, we conditionally inactivated Dnmt3a and Dnmt3b in hematopoietic lineages in mice. Loss of Dnmt3a but not Dnmt3b in hematopoietic cells induces cellular transformation of B-cells and CLL, suggesting a tumor suppressor function for Dnmt3a in CLL development. The cellular and molecular basis of this function remains unclear. We hypothesize that the tumor suppressor function of Dnmt3a depends on DNA methylase activity, whose loss results in promoter hypomethylation and up-regulation of genes functioning as epigenetic drivers of CLL. Three Specific Aims will address this: In Aim 1 we will identify and characterize cancer-initiating cells in CLL induced by Dnmt3a deficiency and analyze their biological and molecular properties. In Aim 2 we will determine whether Dnmt3a methyltransferases activity or rather methylation -independent repressor activity is responsible for its tumor suppressor function. In Aim 3 we will test the ability of selected Dnmt3a target genes to induce CLL in vivo and evaluate their roles in maintenance of the tumor phenotype in human CLL cell lines in vitro. A careful analysis of the tumor suppressor function of Dnmt3a will provide useful insight into biological and molecular events governing the development of mouse and human CLL.

描述（由应用提供）：慢性淋巴细胞性白血病（CLL）是一种异质的B细胞恶性肿瘤，与迄今为止确定的癌素，病毒，辐射或潜在的遗传缺陷无关。该疾病的特征是造血组织中成熟的B细胞积累，目前是无法治愈的。哺乳动物基因组DNA的胞嘧啶甲基化对于正常生理过程至关重要，因为它对大量基因的转录调节有效。对人类CLL样品的最新基因组分析表明，基因组的编码部分的全球低甲基化，表明DNA甲基转移酶（DNMT）参与了疾病的发病机理。为了诱导低甲基化，我们在小鼠造血谱系中有条件地灭活DNMT3A和DNMT3B。造血细胞中DNMT3A的丧失，但不丧失DNMT3B，诱导B细胞和CLL的细胞转化，这表明DNMT3A在CLL发育中具有抑制DNMT3A的肿瘤功能。该功能的细胞和分子基础尚不清楚。我们假设DNMT3A的肿瘤抑制剂功能取决于DNA甲基酶活性，DNA甲基酶活性导致启动子甲基化和作为CLL表观遗传驱动因素起作用的基因上调。三个具体目标将解决以下方面：在AIM 1中，我们将确定并表征癌症的癌症 DNMT3A缺乏诱导的CLL细胞并分析其生物学和分子特性。在AIM 2中，我们将确定DNMT3A甲基转移酶的活性或甲基化非依赖性复制剂活性是否负责其肿瘤抑制器功能。在AIM 3中，我们将测试选定的DNMT3A靶基因在体内影响CLL的能力，并评估其在体外人类CLL细胞系中维持肿瘤表型中的作用。对DNMT3A的肿瘤抑制功能的仔细分析将为有关小鼠和人类CLL发展的生物学和分子事件提供有用的见解。