Attenuation of AML1-ETO cellular dysregulation correlates with increased leukemogenic potential
Attenuation of AML1-ETO cellular dysregulation correlates with increased leukemogenic potential
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DOI：
10.1182/blood-2012-11-465641
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发表时间：
2013-05-02
期刊：
影响因子：
20.3
通讯作者：
Zhang, Dong-Er
中科院分区：
文献类型：
--
作者：
DeKelver, Russell C.;Yan, Ming;Zhang, Dong-Er
AML 1-ETO（RUNX 1-ETO）融合蛋白由8; 21易位产生，通常见于急性髓性白血病，其融合了AML 1（RUNX 1）和ETO（MTG 8，RUNX 1 T1）基因。以前的研究表明，AML 1-ETO干扰AML 1功能，但需要额外的合作突变，以诱导白血病的发展。在小鼠模型中，缺乏C-末端的AML 1-ETO形式已被证明具有极大增强的致白血病潜力。在这里，我们调查的作用，2 AML 1-ETO C-末端相互作用蛋白，N-CoR，转录辅抑制因子，和SON，剪接/转录因子所需的细胞周期进程，在AML 1-ETO诱导的白血病发展。AML 1-ETO-W 692 A在NHR 4处失去N-CoR结合，表现出减弱的转录抑制能力和降低的细胞失调，并促进体内白血病。这些结果支持AML 1-ETO在细胞转化中失调程度的重要性，并证明AML 1-ETO-W 692 A可用作确定哪些因素损害AML 1-ETO的致白血病潜力的有效实验模型。
AML1-ETO (RUNX1-ETO) fusion proteins are generated by the 8; 21 translocation, commonly found in acute myeloid leukemia, which fuses the AML1 (RUNX1) and ETO (MTG8, RUNX1T1) genes. Previous studies have shown that AML1-ETO interferes with AML1 function but requires additional cooperating mutations to induce leukemia development. In mouse models, AML1-ETO forms lacking the C-terminus have been shown to have greatly enhanced leukemogenic potential. Here, we investigate the role of 2 AML1-ETO C-terminal-interacting proteins, N-CoR, a transcriptional corepressor, and SON, a splicing/transcription factor required for cell cycle progression, in AML1-ETO-induced leukemia development. AML1-ETO-W692A loses N-CoR binding at NHR4, displays attenuated transcriptional repression ability and decreased cellular dysregulation, and promotes leukemia in vivo. These results support the importance of the degree of dysregulation by AML1-ETO in cellular transformation and demonstrate that AML1-ETO-W692A can be used as an effective experimental model for determining which factors compromise the leukemogenic potential of AML1-ETO.