AML1-ETO expression is directly involved in the development of acute myeloid leukemia in the presence of additional mutations

The t(8;21) is one of the most frequent chromosomal abnormalities associate d with acute myeloid leukemia (AML). The translocation, which involves the AML1 gene on chromosome 21 and the ETO gene on chromosome 8, generates an A ML1-ETO fusion transcription factor. To examine the effect of the AML1-ETO fusion protein on leukemogenesis, we made transgenic mice in which expressi on 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 no t 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 litterma tes developed acute T lymphoblastic leukemia. Our results provide direct ev idence that AML1-ETO is critical for causing myeloid leukemia, but one or m ore additional mutations are required for leukemogenesis. The hMRP8-ALM1-ET O-transgenic mice provide an excellent model that can be used to isolate ad ditional genetic events and to further understand the molecular pathogenesi s of AML1-ETO-related leukemia.