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.The t(8;21)(q22;q22) translocation, which fuses the ETO gene on human chromosome 8 with the AML1 gene on chromosome 21, is seen in approximately 12 to 15% of acute myelogenous leukemia (AML) cases and in about 40% of AML cases with a French-American-British classified M2 phenotype (10, 27). AML1 (also known as Runx1) is a transcription factor with significant homology to the product of the Drosophila segmentation gene Runt (11,23). It binds the enhancer core target sequence, TGT/cGGT, in association with a non-DNAbinding subunit, CBF (5,20,28,40). Both proteins (together referred to as core-binding factor [CBF]) interact through the DNA-binding, Runt homology domain of AML1. The inversion (16) disrupts the CBF gene and is found in an additional 12% of AML cases (18). Null mutations in either CBF subunit in mice resulted in embryonic lethality that was associated with intracranial hemorrhaging and a complete absence of definitive hematopoiesis (30,36,38,39).The t(8;21) translocation fuses the N-terminal 177 amino acids of AML1, which includes the Runt homology domain that binds DNA and interacts with CBF, in frame with amino acids 30 to 604 of ETO. The fusion protein deletes the Cterminal activation domain of AML1. The ETO gene is homologous to the Drosophila gene nervy and can associate with transcriptional corep...
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