Chromosome fragility and translocations in lymphocytes

淋巴细胞中的染色体脆性和易位

基本信息

批准号：
8863191
负责人：
Davide Filippo Robbiani
金额：
$ 21.19万
依托单位：
ROCKEFELLER UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-02-01 至 2017-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8863191
关键词：
Activated B-Lymphocyte Acute T Cell Leukemia Affinity Antibodies B-Cell Activation B-Cell Acute Lymphoblastic Leukemia B-Cell Development B-Lymphocytes BCL2 gene BCL9 gene Biochemical Biological Bone Marrow Breast Burkitt Lymphoma CCND1 gene Cancer Etiology Cell Culture Techniques Cells Chromatin Chromosomal Instability Chromosomal translocation Chromosome Deletion Chromosome Fragility Chromosomes Code Collection Complex DNA DNA Binding DNA Damage DNA Double Strand Break DNA Sequence DNA Sequence Rearrangement DNA Structure DNA biosynthesis Follicular Lymphoma Gene Rearrangement Generations Genes Genetic Recombination Genome Genomic Instability Genomics Goals Histones Human Human Characteristics IGH@ gene cluster IgK Immune response Immunoglobulin Class Switching Immunoglobulin Genes Immunoglobulin Switch Recombination Label Lead Lymphocyte Lymphoma MYC gene Malignant Neoplasms Methods Molecular Mus Mutate Oncogenes Oncogenic Peptide Signal Sequences Physiological Predisposing Factor Proliferating Prostate Reaction Recruitment Activity Recurrence Research Role Site Source Structure of germinal center of lymph node T-Lymphocyte Techniques Testing Time Transgenic Organisms Ursidae Family V(D)J Recombination activation-induced cytidine deaminase c-myc Genes cofactor deep sequencing genome integrity genome-wide leukemia/lymphoma lung Carcinoma novel overexpression pathogen programs public health relevance recombinase research study tumor

项目摘要

DESCRIPTION (provided by applicant): Chromosome fragility and translocations in lymphocytes Summary DNA double-strand breaks pose a particularly serious threat to genome integrity, as they predispose to chromosome rearrangements, which can lead to cancer. Recurrent chromosome translocations and deletions are found across a multitude of malignancies (such as lymphomas, leukemias, and carcinomas of the lung, breast and prostate) and involve hundreds of cancer genes (1, 2). However, little is known about the molecular mechanisms governing these aberrant DNA recombinations, and particularly about the cause of fragility of specific genes. Under physiologic conditions, programmed DNA breaks are obligate intermediates during the assembly and diversification reactions of antibody genes. The RAG1/2 recombinase breaks DNA in developing lymphocytes during the assembly of the variable gene segments (V(D)J recombination). In activated B cells, Activation-Induced cytidine Deaminase (AID) causes DNA breaks while altering antibody effector functions during class switch recombination (CSR). Tumors of lymphocytes (lymphomas) often bear hallmark oncogenic translocations involving antibody genes, and the physiologically occurring DNA breaks at these loci are thought to be a predisposing factor (3, 4). However, the source of DNA damage at the oncogene partners involved in these translocations is less clear. B lymphocytes are rapidly dividing cells that proliferate in distinct bursts: first during B cell development in the bone marrow at a time when RAG1/2 is expressed, and later in germinal centers when AID is expressed. RAG1/2, AID and DNA replication are all associated with DNA damage (5, 6). AID causes DNA breaks at the c-myc oncogene and lymphoma-associated chromosome translocations (7, 8). Moreover, AID causes collateral DNA damage at hundreds of other genes in activated B cells, and genome- wide DNA breaks by AID can lead to chromosome deletions and translocations, including some that are found in human B cell lymphoma (9, 10). In contrast, despite a large body of circumstantial evidence, the parameters by which RAG1/2 is mistargeted to generate lymphomagenic aberrations remain not well understood. In two specific aims we propose to test the hypothesis that RAG1/2 damages the B cell genome by mechanisms that are not limited to its action at RSS sites. First, we will examine the DNA damage by RAG1/2 to the genome of primary developing B cells. Second, we will define the landscape of RAG1/2 induced chromosome rearrangements. The long-term goal of the proposed research is to obtain a comprehensive molecular understanding of the genesis of chromosome translocations in B lymphocytes.

描述（由申请人提供）：淋巴细胞中的染色体脆性和易位摘要 DNA 双链断裂对基因组完整性构成特别严重的威胁，因为它们容易发生染色体重排，从而导致癌症中反复出现的染色体易位和缺失。多种恶性肿瘤（例如淋巴瘤、白血病以及肺癌、乳腺癌和前列腺癌）并涉及数百种癌症基因 (1, 2) 然而，人们知之甚少。关于控制这些异常 DNA 重组的分子机制，特别是关于特定基因脆弱性的原因，在生理条件下，程序性 DNA 断裂是抗体基因组装和多样化反应过程中的必然中间体，RAG1/2 重组酶在发育过程中断裂 DNA。淋巴细胞在可变基因片段组装（V(D)J 重组）过程中，在活化的 B 细胞中，激活诱导的胞苷脱氨酶 (AID) 会导致 DNA 断裂。在类别转换重组 (CSR) 过程中改变抗体效应子功能淋巴细胞肿瘤（淋巴瘤）通常具有涉及抗体基因的标志性致癌易位，并且这些位点上发生的生理性 DNA 断裂被认为是诱发因素 (3, 4)。参与这些易位的癌基因伙伴的 DNA 损伤来源尚不清楚。B 淋巴细胞是快速分裂的细胞，它们以不同的爆发方式增殖：首先是在骨骼中 B 细胞发育期间。当 RAG1/2 表达时在骨髓中，以及当 AID 表达时在生发中心，AID 和 DNA 复制都与 DNA 损伤相关 (5, 6)。癌基因和淋巴瘤相关染色体易位 (7, 8) 此外，AID 会导致活化 B 细胞中数百个其他基因的附带 DNA 损伤，并且 AID 造成的全基因组 DNA 断裂可导致染色体缺失和易位，包括在人类 B 细胞淋巴瘤中发现的一些 (9, 10) 相比之下，尽管有大量间接证据，但我们在两个具体目标中仍不清楚 RAG1/2 被误定位而产生淋巴瘤发生畸变的参数。提议检验 RAG1/2 通过不限于其在 RSS 位点的作用的机制损伤 B 细胞基因组的假设。首先，我们将检查 RAG1/2 对初级发育 B 细胞基因组的 DNA 损伤。其次，我们将定义 RAG1/2 诱导的染色体重排的情况。拟议研究的长期目标是全面了解 B 淋巴细胞染色体易位的发生机制。