Park Sangho, Chen Wei, Cierpicki Tomasz, Tonelli Marco, Cai Xiongwei, Speck Nancy A, Bushweller John H
Department of Molecular Physiology and Biological Physics, University of Virginia, Charlottesville, VA 22908, USA.
Blood. 2009 Apr 9;113(15):3558-67. doi: 10.1182/blood-2008-06-161307. Epub 2009 Feb 9.
AML1-ETO is the chimeric protein product of the t(8;21) in acute myeloid leukemia. The ETO portion of the fusion protein includes the eTAFH domain, which is homologous to several TATA binding protein-associated factors (TAFs) and interacts with E proteins (E2A and HEB). It has been proposed that AML1-ETO-mediated silencing of E protein function might be important for t(8;21) leukemogenesis. Here, we determined the solution structure of a complex between the AML1-ETO eTAFH domain and an interacting peptide from HEB. On the basis of the structure, key residues in AML1-ETO for HEB association were mutated. These mutations do not impair the ability of AML1-ETO to enhance the clonogenic capacity of primary mouse bone marrow cells and do not eliminate its ability to repress proliferation or granulocyte differentiation. Therefore, the eTAFH-E protein interaction appears to contribute relatively little to the activity of AML1-ETO.
AML1-ETO是急性髓系白血病中t(8;21)的嵌合蛋白产物。融合蛋白的ETO部分包含eTAFH结构域，该结构域与几种TATA结合蛋白相关因子（TAFs）同源，并与E蛋白（E2A和HEB）相互作用。有人提出，AML1-ETO介导的E蛋白功能沉默可能对t(8;21)白血病发生很重要。在此，我们确定了AML1-ETO eTAFH结构域与来自HEB的相互作用肽之间复合物的溶液结构。基于该结构，对AML1-ETO中与HEB结合的关键残基进行了突变。这些突变并不损害AML1-ETO增强原代小鼠骨髓细胞克隆形成能力的能力，也不消除其抑制增殖或粒细胞分化的能力。因此，eTAFH-E蛋白相互作用似乎对AML1-ETO的活性贡献相对较小。
