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: 6745593
• 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/6745593
• 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 靶向免疫球蛋白（IG）基因座的易位允许免疫球蛋白（IG）基因的表达。 正常和恶性肿瘤发生中重要基因的鉴定 B细胞我们克隆了一个高度保守的锌指基因位点BCL 11 A， 一种染色体易位，t（2;14）（p13;q32.3），作为唯一的 CLL中罕见和临床侵袭性亚群的细胞遗传学异常。所有 断裂点涉及IG γ开关区域和CpG岛的5'端聚集 与BCL 11 A有关。BCL 11 A与REL紧密地端粒映射，并且还出现 作为2 p13基因扩增和获得的靶基因， 霍奇金病和结节性B-NHL。这些数据表明 BCL 1 1A在不同亚型肺癌发病机制中的表达失调 侵袭性人类癌症有三种常见的BCL 11 A同种型;每一种都是一种 转录抑制因子和不同的锌指的数量。BCL11A 与BCL 6有物理相互作用，并与BCL 6有几个相似之处， 经常转移到IG和非IG相关位点。BCL 1 1A股 与染色体14q32.1上的人类家族成员BCL 11B具有高度同一性， 在后生动物进化过程中有同源物。我们建议研究临床 BCL-11表达失调在恶性肿瘤中意义 染色体2 p13的异常，并确定BCL 11的功能， 正常和恶性B细胞发育具体方法包括筛查 对于额外（BCL 11 A）和初始（BCL 11B）病例， 这些基因座的断裂/扩增;转录因子的功能分析 机制和下游目标;评估转化活动 体外和转基因模型;以及通过靶向的 破坏