Chromosome 5q deletion and epigenetic suppression of the gene encoding α-catenin (CTNNA1) in myeloid cell transformation
Chromosome 5q deletion and epigenetic suppression of the gene encoding α-catenin (CTNNA1) in myeloid cell transformation
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DOI：
10.1038/nm1512
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发表时间：
2007-01-01
期刊：
影响因子：
82.9
通讯作者：
Look, A. Thomas
中科院分区：
文献类型：
--
作者：
Liu, Ting Xi;Becker, Michael W.;Look, A. Thomas
5号染色体长臂的全部或部分间质缺失（del(5q)）是人类骨髓增生异常综合征（MDS，一种白血病前期疾病）和急性髓性白血病（AML）中常见的克隆性染色体异常(1)，并且被认为是通过删除一个或多个肿瘤抑制基因导致这些疾病的发病机制(2)。虽然在染色体带5q31.1上发现了一个主要的共缺失区（CDR）（参考文献）。3-7)，试图在这一波段内识别肿瘤抑制因子是不成功的。我们重点分析了原始白血病起始细胞的RNA基因表达，其中含有5q缺失（8,9），并分析了CDR中正常造血干细胞表达的12个基因。本研究表明，编码α -连环蛋白（CTNNA1）的基因在5q缺失的AML或MDS患者的白血病起始干细胞中的表达水平远低于缺乏5q缺失的MDS或AML患者或正常造血干细胞中的表达水平。对5q31区域缺失的髓系白血病HL-60细胞的分析（10,11）表明，保留等位基因的CTNNA1启动子受到甲基化和组蛋白去乙酰化的抑制。恢复CTNNA1在HL-60细胞中的表达，导致增殖减少和凋亡细胞死亡。因此，造血干细胞中α -catenin肿瘤抑制因子的表达缺失可能提供了促进人类MDS或del AML的生长优势（5q）。
m Interstitial loss of all or part of the long arm of chromosome 5, or del(5q), is a frequent clonal chromosomal abnormality in human myelodysplastic syndrome (MDS, a preleukemic disorder) and acute myeloid leukemia (AML)(1), and is thought to contribute to the pathogenesis of these diseases by deleting one or more tumor-suppressor genes(2). Although a major commonly deleted region (CDR) has been delineated on chromosome band 5q31.1 (refs.3-7), attempts to identify tumor suppressors within this band have been unsuccessful. We focused our analysis of gene expression on RNA from primitive leukemia-initiating cells, which harbor 5q deletions(8,9), and analyzed 12 genes within the CDR that are expressed by normal hematopoietic stem cells. Here we show that the gene encoding alpha-catenin (CTNNA1) is expressed at a much lower level in leukemia-initiating stem cells from individuals with AML or MDS with a 5q deletion than in individuals with MDS or AML lacking a 5q deletion or in normal hematopoietic stem cells. Analysis of HL-60 cells, a myeloid leukemia line with deletion of the 5q31 region(10,11), showed that the CTNNA1 promoter of the retained allele is suppressed by both methylation and histone deacetylation. Restoration of CTNNA1 expression in HL-60 cells resulted in reduced proliferation and apoptotic cell death. Thus, loss of expression of the alpha-catenin tumor suppressor in hematopoietic stem cells may provide a growth advantage that contributes to human MDS or AML with del(5q).