BCL11 GENES IN NORMAL AND MALIGNANT B CELL DEVELOPMENT

正常和恶性 B 细胞发育中的 BCL11 基因

• 批准号: 6364329
• 负责人: HALEY O TUCKER
• 金额: $ 23.63万
• 依托单位: UNIVERSITY OF TEXAS AT AUSTIN
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-05-01 至 2006-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6364329
• 关键词: B lymphocyte; Hodgkin's disease; artificial chromosomes; chronic lymphocytic leukemia; developmental genetics; embryogenesis; fluorescent in situ hybridization; gene induction /repression; gene targeting; genetically modified animals; immunogenetics; laboratory mouse; leukopoiesis; microarray technology; monoclonal antibody; natural gene amplification; neoplasm /cancer genetics; nonHodgkin's lymphoma; protein isoforms; protein protein interaction; southern blotting; transcription factor

DESCRIPTION (provided by applicant): Molecular cloning of chromosomal translocations targeted to the immunoglobulin (IG) loci allows the identification of genes of importance in the genesis of normal and malignant B-cells. We have cloned a highly conserved zinc finger gene locus BCL11A, from a chromosomal translocation, t(2;14)(p13;q32.3), that occurs as the sole cytogenetic abnormality in rare and clinically aggressive subset of CLL. All breakpoints involved IG gamma switch regions and clustered 5' of a CpG island associated with BCL11A. BCL11A maps closely telomeric to REL and also appears to be a target gene for amplifications and gains of 2p13 observed frequently in Hodgkin's disease and in extranodal B-NHL. Together the data implicate deregulated expression of BCL1 1A in the pathogenesis of divergent subtypes of aggressive human cancers. There are three common BCL11A isoforms; each is a transcriptional repressor and varies in the number of zinc fingers. BCL11A interacts physically with and shares several similarities with BCL6, a gene frequently translocated to both IG and non-IG associated sites. BCL1 1A shares high identity with a human family member, BCL11B, on chromosome 14q32.1 and with homologues across metazoan evolution. We propose to study the clinical significance of deregulation BCL11 expression in malignancies with abnormalities of chromosome 2p13 and to determine the function of BCL11 in normal and malignant B-cell development Specific approaches include screening for additional (BCL1 1A) and initial (BCL11B) cases containing breaks/amplifications a these loci; functional analysis of transcriptional mechanisms an downstream targets; assessing transforming activities using in vitro and transgenic models; and inactivating the gene by targeted disruption.

描述（由申请人提供）：染色体的分子克隆 针对免疫球蛋白（IG）基因座的易位允许 鉴定正常和恶性的起源中重要性的基因 B细胞。我们从来自 染色体易位，t（2; 14）（p13; q32.3），以唯一 CLL的罕见和临床攻击性子集中的细胞遗传学异常。全部 断点涉及IG伽马开关区域，并聚集了一个CpG岛的5' 与Bcl11a相关。 Bcl11a地图紧密端粒至REL，也出现 成为一个靶基因，以进行2p13的扩增和收益。 霍奇金氏病和外道B-NHL。在一起的数据牵涉 Bcl1 1a的放松调节表达在发散亚型的发病机理中 激进的人类癌症。有三种常见的Bcl11a同工型；每个都是一个 转录阻遏物和锌指的数量各不相同。 Bcl11a 与Bcl6（基因 经常转移到IG和非Ig相关位点。 BCl1 1A股票 与人类家庭成员Bcl11b，染色体14q32.1和 跨后生动物进化的同源物。我们建议研究临床 放松管制BCl11表达在恶性肿瘤中的重要性 2p13染色体的异常，并确定Bcl11在 正常和恶性B细胞开发特定方法包括筛查 用于附加（BCl1 1a）和初始（BCL11B）案例 这些基因座的断裂/扩增；转录的功能分析 机制下游目标；使用IN评估转型活动 体外和转基因模型；并通过目标灭活基因 破坏。