Wang J, Hoshino T, Redner R L, Kajigaya S, Liu J M
Hematology Branch, National Heart, Lung, and Blood Institute, Bethesda MD 20892, USA.
Proc Natl Acad Sci U S A. 1998 Sep 1;95(18):10860-5. doi: 10.1073/pnas.95.18.10860.
The t(8;21) translocation between two genes known as AML1 and ETO is seen in approximately 12-15% of all acute myeloid leukemia (AML) and is the second-most-frequently observed nonrandom genetic alteration associated with AML. AML1 up-regulates a number of target genes critical to normal hematopoiesis, whereas the AML1/ETO fusion interferes with this trans-activation. We discovered that the fusion partner ETO binds to the human homolog of the murine nuclear receptor corepressor (N-CoR). The interaction is mediated by two unusual zinc finger motifs present at the carboxyl terminus of ETO. Human N-CoR (HuN-CoR), which we cloned and sequenced in its entirety, encodes a 2,440-amino acid polypeptide and has a central domain that binds ETO. N-CoR, mammalian Sin3 (mSin3A and B), and histone deacetylase 1 (HDAC1) form a complex that alters chromatin structure and mediates transcriptional repression by nuclear receptors and by a number of oncoregulatory proteins. We found that ETO, through its interaction with the N-CoR/mSin3/HDAC1 complex, is also a potent repressor of transcription. This observation provides a mechanism for how the AML1/ETO fusion may inhibit expression of AML1-responsive target genes and disturb normal hematopoiesis.
在所有急性髓性白血病（AML）中，约12% - 15%的病例存在被称为AML1和ETO的两个基因之间的t(8;21)易位，这是与AML相关的第二常见的非随机基因改变。AML1上调许多对正常造血至关重要的靶基因，而AML1/ETO融合蛋白会干扰这种反式激活。我们发现融合伴侣ETO与小鼠核受体共抑制因子（N-CoR）的人类同源物结合。这种相互作用由ETO羧基末端存在的两个不寻常的锌指基序介导。我们对人类N-CoR（HuN-CoR）进行了完整的克隆和测序，它编码一个2440个氨基酸的多肽，并且有一个结合ETO的中央结构域。N-CoR、哺乳动物Sin3（mSin3A和B）和组蛋白去乙酰化酶1（HDAC1）形成一个复合物，该复合物改变染色质结构，并介导核受体和许多癌调节蛋白的转录抑制。我们发现，ETO通过与N-CoR/mSin3/HDAC1复合物相互作用，也是一种有效的转录抑制因子。这一观察结果为AML1/ETO融合蛋白如何抑制AML1反应性靶基因的表达并扰乱正常造血提供了一种机制。
