Yuan Y, Zhou L, Miyamoto T, Iwasaki H, Harakawa N, Hetherington C J, Burel S A, Lagasse E, Weissman I L, Akashi K, Zhang D E
Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA 92037, USA.
Proc Natl Acad Sci U S A. 2001 Aug 28;98(18):10398-403. doi: 10.1073/pnas.171321298.
The t(8;21) is one of the most frequent chromosomal abnormalities associated with acute myeloid leukemia (AML). The translocation, which involves the AML1 gene on chromosome 21 and the ETO gene on chromosome 8, generates an AML1-ETO fusion transcription factor. To examine the effect of the AML1-ETO fusion protein on leukemogenesis, we made transgenic mice in which expression of AML1-ETO is under the control of the human MRP8 promoter (hMRP8-AML1-ETO). AML1-ETO is specifically expressed in myeloid cells, including common myeloid progenitors of hMRP8-AML1-ETO transgenic mice. The transgenic mice were healthy during their life spans, suggesting that AML1-ETO alone is not sufficient for leukemogenesis. However, after treatment of newborn hMRP8-AML1-ETO transgenic mice and their wild-type littermates with a strong DNA-alkylating mutagen, N-ethyl-N-nitrosourea, 55% of transgenic mice developed AML and the other 45% of transgenic mice and all of the wild-type littermates developed acute T lymphoblastic leukemia. Our results provide direct evidence that AML1-ETO is critical for causing myeloid leukemia, but one or more additional mutations are required for leukemogenesis. The hMRP8-AML1-ETO-transgenic mice provide an excellent model that can be used to isolate additional genetic events and to further understand the molecular pathogenesis of AML1-ETO-related leukemia.
t(8;21)是与急性髓系白血病（AML）相关的最常见染色体异常之一。这种易位涉及21号染色体上的AML1基因和8号染色体上的ETO基因，产生一种AML1-ETO融合转录因子。为了研究AML1-ETO融合蛋白对白血病发生的影响，我们制作了转基因小鼠，其中AML1-ETO的表达受人类MRP8启动子（hMRP8-AML1-ETO）的控制。AML1-ETO在髓系细胞中特异性表达，包括hMRP8-AML1-ETO转基因小鼠的常见髓系祖细胞。这些转基因小鼠在其寿命期间健康，这表明单独的AML1-ETO不足以引发白血病。然而，在用强DNA烷化诱变剂N-乙基-N-亚硝基脲处理新生的hMRP8-AML1-ETO转基因小鼠及其野生型同窝仔鼠后，55%的转基因小鼠发生了AML，另外45%的转基因小鼠和所有野生型同窝仔鼠发生了急性T淋巴细胞白血病。我们的结果提供了直接证据，表明AML1-ETO对于导致髓系白血病至关重要，但白血病发生还需要一个或多个额外的突变。hMRP8-AML1-ETO转基因小鼠提供了一个极好的模型，可用于分离其他遗传事件并进一步了解AML1-ETO相关白血病的分子发病机制。
