Analysis of the role of AML1-ETO in leukemogenesis, using an Inducible transgenic mouse model

As reported previously, AML1-ETO knock-in mice were generated to investigat e 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 hemorrh aging 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 wh ich the expression of AML1-ETO is under the control of a tetracycline-induc ible 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 expres sed in the bone marrow of AML1-ETO and tet-controlled transcriptional activ ator double-positive transgenic mice, Furthermore, the addition of tetracyc line reduces AML1-ETO expression in double-positive mice to nondetectable l evels. 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 animal s. These results demonstrate that AML1-ETO has a very restricted capacity t o transform cells. Either the introduction of additional genetic changes or the expression of AML1-ETO at a particular stage of hematopoietic cell dif ferentiation will be necessary to develop a model for studying the pathogen esis of t(8;21), (Blood. 2000;96:2108-2115) (C) 2000 by The American Societ y of Hematology.