Imai Y, Kurokawa M, Izutsu K, Hangaishi A, Takeuchi K, Maki K, Ogawa S, Chiba S, Mitani K, Hirai H
Department of Hematology and Oncology and the Department of Pathology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.
Blood. 2000 Nov 1;96(9):3154-60.
The AML1 gene encodes a DNA-binding protein that contains the runt domain and is the most frequent target of translocations associated with human leukemias. Here, point mutations of the AML1 gene, V105ter (single-letter amino acid code) and R139G, (single-letter amino acid codes) were identified in 2 cases of myelodysplastic syndrome (MDS) by means of the reverse transcriptase-polymerase chain reaction single-strand conformation polymorphism method. Both mutations are present in the region encoding the runt domain of AML1 and cause loss of the DNA-binding ability of the resultant products. Of these mutants, V105ter has also lost the ability to heterodimerize with polyomavirus enhancer binding protein 2/core binding factor beta (PEBP2beta/CBFbeta). On the other hand, the R139G mutant acts as a dominant negative inhibitor by competing with wild-type AML1 for interaction with PEBP2beta/CBFbeta. This study is the first report that describes mutations of AML1 in patients with MDS and the mechanism whereby the mutant acts as a dominant negative inhibitor of wild-type AML1.
AML1基因编码一种含有 runt 结构域的 DNA 结合蛋白，它是与人类白血病相关的易位最常见的靶点。在此，通过逆转录聚合酶链反应单链构象多态性方法，在 2 例骨髓增生异常综合征（MDS）患者中鉴定出 AML1 基因的点突变 V105ter（单字母氨基酸代码）和 R139G（单字母氨基酸代码）。这两种突变均存在于编码 AML1 runt 结构域的区域，导致所得产物丧失 DNA 结合能力。在这些突变体中，V105ter 也失去了与多瘤病毒增强子结合蛋白 2/核心结合因子β（PEBP2β/CBFβ）异源二聚化的能力。另一方面，R139G 突变体通过与野生型 AML1 竞争与 PEBP2β/CBFβ 的相互作用，作为显性负抑制剂发挥作用。本研究是首次报道 MDS 患者中 AML1 的突变以及突变体作为野生型 AML1 显性负抑制剂的作用机制。
