The t(8;21) fusion protein, AML1-ETO, specifically represses the transcription of the p14ARF tumor suppressor in acute myeloid leukemia
The t(8;21) fusion protein, AML1-ETO, specifically represses the transcription of the p14ARF tumor suppressor in acute myeloid leukemia
复制标题
DOI：
10.1038/nm726
复制
发表时间：
2002-07-01
期刊：
影响因子：
82.9
通讯作者：
Hiebert, SW
中科院分区：
文献类型：
--
作者：
Linggi, B;Müller-Tidow, C;Hiebert, SW
t（8; 21）是与急性白血病相关的最常见的染色体易位之一。该易位产生由急性髓性白血病-1转录因子和8 - 21辅阻遏物（AML 1-ETO）组成的融合蛋白，其通过AML 1（RUNX 1）DNA结合位点抑制转录并使造血祖细胞永生化。我们已经确定了p14（ARF）肿瘤抑制因子，p53癌基因检查点的介质，作为AML 1-ETO的直接转录靶点。AML 1-ETO抑制p14（ARF）启动子并降低多种细胞类型中p14（ARF）表达的内源性水平。相反，AML 1刺激p14（ARF）的表达和诱导的表型与细胞衰老一致。染色质免疫沉淀试验证明AML 1-ETO与p14（ARF）启动子特异性结合。在含有t（8; 21）的急性髓性白血病样本中，p14（ARF）mRNA水平明显低于其他缺乏这种易位的急性髓性白血病。p14（ARF）的抑制可以解释为什么p53在含t（8; 21）的白血病中没有突变，并表明p14（ARF）在大量人类白血病中是重要的肿瘤抑制因子。
The t( 8; 21) is one of the most frequent chromosomal translocations associated with acute leukemia. This translocation creates a fusion protein consisting of the acute myeloid leukemia-1 transcription factor and the eight-twenty-one corepressor (AML1-ETO), which represses transcription through AML1 (RUNX1) DNA binding sites and immortalizes hematopoietic progenitor cells. We have identified the p14(ARF) tumor suppressor, a mediator of the p53 oncogene checkpoint, as a direct transcriptional target of AML1-ETO. AML1-ETO repressed the p14(ARF) promoter and reduced endogenous levels of p14(ARF) expression in multiple cell types. In contrast, AML1 stimulated p14(ARF) expression and induced phenotypes consistent with cellular senescence. Chromatin immunoprecipitation assays demonstrated that AML1-ETO was specifically bound to the p14(ARF) promoter. In acute myeloid leukemia samples containing the t( 8; 21), levels of p14(ARF) mRNA were markedly lower when compared with other acute myeloid leukemias lacking this translocation. Repression of p14(ARF) may explain why p53 is not mutated in t( 8; 21)-containing leukemias and suggests that p14(ARF) is an important tumor suppressor in a large number of human leukemias.