Yergeau D A, Hetherington C J, Wang Q, Zhang P, Sharpe A H, Binder M, Marín-Padilla M, Tenen D G, Speck N A, Zhang D E
Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA.
Nat Genet. 1997 Mar;15(3):303-6. doi: 10.1038/ng0397-303.
Acute myeloid leukaemia (AML) is a major haematopoietic malignancy characterized by the proliferation of a malignant clone of myeloid progenitor cells. A reciprocal translocation, t(8;21)(q22;q22), observed in the leukaemic cells of approximately 40% of patients with the M2 subtype of AML disrupts both the AML1 (CBFA2) gene on chromosome 21 and the ETO (MTG8) gene on chromosome 8 (refs 3-5). A chimaeric protein is synthesized from one of the derivative chromosomes that contains the N terminus of the AML1 transcription factor, including its DNA-binding domain, fused to most of ETO, a protein of unknown function. We generated mice that mimic human t(8;21) with a "knock-in' strategy. Mice heterozygous for an AML1-ETO allele (AML1-ETO/+) die in midgestation from haemorrhaging in the central nervous system and exhibit a severe block in fetal liver haematopoiesis. This phenotype is very similar to that resulting from homozygous disruption of the AML1 (Cbfa2) or Cbfb genes, indicating that AML1-ETO blocks normal AML1 function. However, yolk sac cells from AML1-ETO/+ mice differentiated into macrophages in haematopoietic colony forming unit (CFU) assays, unlike Cbfa2-/- or Cbfb-/-cells, which form no colonies in vitro. This indicates that AML1-ETO may have other functions besides blocking wild-type AML1, a property that may be important in leukaemogenesis.
急性髓系白血病（AML）是一种主要的造血系统恶性肿瘤，其特征是髓系祖细胞的恶性克隆增殖。在大约40%的AML M2亚型患者的白血病细胞中观察到一种相互易位，即t(8;21)(q22;q22)，它破坏了21号染色体上的AML1（CBFA2）基因和8号染色体上的ETO（MTG8）基因（参考文献3 - 5）。一种嵌合蛋白由其中一条衍生染色体合成，该染色体包含AML1转录因子的N端，包括其DNA结合结构域，与大部分ETO融合，ETO是一种功能未知的蛋白质。我们采用“敲入”策略生成了模拟人类t(8;21)的小鼠。AML1 - ETO等位基因杂合的小鼠（AML1 - ETO/+）在妊娠中期因中枢神经系统出血而死亡，并在胎儿肝脏造血过程中表现出严重阻滞。这种表型与AML1（Cbfa2）或Cbfb基因纯合缺失导致的表型非常相似，表明AML1 - ETO阻断了正常的AML1功能。然而，与Cbfa2 - / - 或Cbfb - / - 细胞不同，AML1 - ETO/+小鼠的卵黄囊细胞在造血集落形成单位（CFU）试验中分化为巨噬细胞，Cbfa2 - / - 或Cbfb - / - 细胞在体外不形成集落。这表明AML1 - ETO除了阻断野生型AML1外可能还有其他功能，这一特性在白血病发生过程中可能很重要。
