de Guzman Cristina G, Warren Alan J, Zhang Zheng, Gartland Larry, Erickson Paul, Drabkin Harry, Hiebert Scott W, Klug Christopher A
Department of Human Genetics, University of Alabama at Birmingham, 1824 6th Avenue South, Birmingham, AL 35294, USA.
Mol Cell Biol. 2002 Aug;22(15):5506-17. doi: 10.1128/MCB.22.15.5506-5517.2002.
The t(8;21)(q22;q22) translocation, which fuses the ETO gene on human chromosome 8 with the AML1 gene on chromosome 21 (AML1-ETO), is one of the most frequent cytogenetic abnormalities associated with acute myelogenous leukemia (AML). It is seen in approximately 12 to 15% of AML cases and is present in about 40% of AML cases with a French-American-British classified M2 phenotype. We have generated a murine model of the t(8;21) translocation by retroviral expression of AML1-ETO in purified hematopoietic stem cells (HSC). Animals reconstituted with AML1-ETO-expressing cells recapitulate the hematopoietic developmental abnormalities seen in the bone marrow of human patients with the t(8;21) translocation. Primitive myeloblasts were increased to approximately 10% of bone marrow by 10 months posttransplant. Consistent with this observation was a 50-fold increase in myeloid colony-forming cells in vitro. Accumulation of late-stage metamyelocytes was also observed in bone marrow along with an increase in immature eosinophilic myelocytes that showed abnormal basophilic granulation. HSC numbers in the bone marrow of 10-month-posttransplant animals were 29-fold greater than in transplant-matched control mice, suggesting that AML1-ETO expression overrides the normal genetic control of HSC pool size. In summary, AMLI-ETO-expressing animals recapitulate many (and perhaps all) of the developmental abnormalities seen in human patients with the t(8;21) translocation, although the animals do not develop leukemia or disseminated disease in peripheral tissues like the liver or spleen. This suggests that the principal contribution of AML1-ETO to acute myeloid leukemia is the inhibition of multiple developmental pathways.
t(8;21)(q22;q22)易位将人类8号染色体上的ETO基因与21号染色体上的AML1基因融合（AML1-ETO），是与急性髓性白血病（AML）相关的最常见细胞遗传学异常之一。在大约12%至15%的AML病例中可见，在法美英分类为M2表型的AML病例中约40%存在。我们通过在纯化的造血干细胞（HSC）中逆转录病毒表达AML1-ETO，建立了t(8;21)易位的小鼠模型。用表达AML1-ETO的细胞重建的动物重现了t(8;21)易位的人类患者骨髓中所见的造血发育异常。移植后10个月，原始髓母细胞增加至骨髓的约10%。与此观察结果一致的是，体外髓系集落形成细胞增加了50倍。骨髓中还观察到晚期晚幼粒细胞的积累，以及显示异常嗜碱性颗粒的未成熟嗜酸性髓细胞增加。移植后10个月的动物骨髓中的HSC数量比移植匹配的对照小鼠高29倍，这表明AML1-ETO的表达超越了HSC池大小的正常遗传控制。总之，表达AML I-ETO的动物重现了t(8;21)易位的人类患者中所见的许多（也许是所有）发育异常，尽管这些动物不会像人类患者那样在肝脏或脾脏等外周组织中发生白血病或播散性疾病。这表明AML1-ETO对急性髓性白血病的主要作用是抑制多种发育途径。
