Rhoades K L, Hetherington C J, Harakawa N, Yergeau D A, Zhou L, Liu L Q, Little M T, Tenen D G, Zhang D E
Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA 92037, USA.
Blood. 2000 Sep 15;96(6):2108-15.
As reported previously, AML1-ETO knock-in mice were generated to investigate the role of AML1-ETO in leukemogenesis and to mimic the progression of t(8;21) leukemia. These knock-in mice died in midgestation because of hemorrhaging in the central nervous system and a block of definitive hematopoiesis during embryogenesis. Therefore, they are not a good model system for the development of acute myeloid leukemia. Therefore, mice were generated in which the expression of AML1-ETO is under the control of a tetracycline-inducible system. Multiple lines of transgenic mice have been produced with the AML1-ETO complementary DNA controlled by a tetracycline-responsive element. In the absence of the antibiotic tetracycline, AML1-ETO is strongly expressed in the bone marrow of AML1-ETO and tet-controlled transcriptional activator double-positive transgenic mice. Furthermore, the addition of tetracycline reduces AML1-ETO expression in double-positive mice to nondetectable levels. Throughout the normal murine lifespan of 24 months, mice expressing AML1-ETO have not developed leukemia. In spite of this, abnormal maturation and proliferation of progenitor cells have been observed from these animals. These results demonstrate that AML1-ETO has a very restricted capacity to transform cells. Either the introduction of additional genetic changes or the expression of AML1-ETO at a particular stage of hematopoietic cell differentiation will be necessary to develop a model for studying the pathogenesis of t(8;21).
如先前报道，为了研究AML1-ETO在白血病发生中的作用并模拟t(8;21)白血病的进展，构建了AML1-ETO基因敲入小鼠。这些基因敲入小鼠在胚胎中期死亡，原因是中枢神经系统出血以及胚胎发育过程中确定性造血受阻。因此，它们不是研究急性髓系白血病发展的良好模型系统。因此，构建了AML1-ETO表达受四环素诱导系统控制的小鼠。已经产生了多系转基因小鼠，其AML1-ETO互补DNA受四环素反应元件控制。在没有抗生素四环素的情况下，AML1-ETO在AML1-ETO和四环素控制的转录激活因子双阳性转基因小鼠的骨髓中强烈表达。此外，添加四环素可将双阳性小鼠中的AML1-ETO表达降低至无法检测的水平。在24个月的正常小鼠寿命期间，表达AML1-ETO的小鼠未发生白血病。尽管如此，从这些动物中观察到祖细胞的异常成熟和增殖。这些结果表明，AML1-ETO转化细胞的能力非常有限。要建立一个研究t(8;21)发病机制的模型，要么引入额外的基因改变，要么在造血细胞分化的特定阶段表达AML1-ETO。
