RUNX1/AML1 DNA-binding domain and ETO/MTG8 NHR2-dimerization domain are critical to AML1-ETO9a leukemogenesis
RUNX1/AML1 DNA-binding domain and ETO/MTG8 NHR2-dimerization domain are critical to AML1-ETO9a leukemogenesis
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DOI：
10.1182/blood-2008-04-153742
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发表时间：
2009-01-22
期刊：
影响因子：
20.3
通讯作者：
Zhang, Dong-Er
中科院分区：
文献类型：
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作者：
Yan, Ming;Ahn, Eun-Young;Zhang, Dong-Er
8；21易位涉及21号染色体上编码RUNX家族DNA结合转录因子AML1(RUNX1)的基因和8号染色体上的ETO(MTG8)基因，产生AML1-ETO融合蛋白。先前的分析表明，全长AML1-ETO阻断了AML1的功能，并需要额外的突变事件来促进白血病的发生。最近，我们从t(8；21)急性髓系白血病(AML)患者样本中鉴定出AML1-ETO的选择性剪接形式，AML1-ETO9a。AML1-ETO9a缺乏AML1-ETO的NHR3和NHR4结构域，在小鼠模型中具有高度的白血病致癌性。在这里，我们报告了AML1-ETO9a诱导AML的关键是AML1DNA结合域和ETO NHR2二聚化结构域，而不是ETO NHR1结构域。NHR1和NHR2之间的区域影响白血病发生的潜伏期。这些结果为进一步分析t(8；21)在白血病发生中的分子机制提供了有价值的见解。(血。2009；113：883-886)
The 8;21 translocation, which involves the gene encoding the RUNX family DNA-binding transcription factor AML1 (RUNX1) on chromosome 21 and the ETO (MTG8) gene on chromosome 8, generates AML1-ETO fusion proteins. Previous analyses have demonstrated that full-length AML1-ETO blocks AML1 function and requires additional mutagenic events to promote leukemia. More recently, we have identified an alternatively spliced form of AML1-ETO, AML1-ETO9a, from t(8;21) acute myeloid leukemia (AML) patient samples. AML1-ETO9a lacks the C-terminal NHR3 and NHR4 domains of AML1-ETO and is highly leukemogenic in the mouse model. Here, we report that the AML1 DNA-binding domain and the ETO NHR2-dimerization domain, but not the ETO NHR1 domain, are critical for the induction of AML by AML1-ETO9a. A region between NHR1 and NHR2 affects latency of leukemogenesis. These results provide valuable insight into further analysis of the molecular mechanism of t(8;21) in leukemogenesis. (Blood. 2009; 113:883-886)