EXPRESSION OF A KNOCKED-IN AML1-ETO LEUKEMIA GENE INHIBITS THE ESTABLISHMENT OF NORMAL DEFINITIVE HEMATOPOIESIS AND DIRECTLY GENERATES DYSPLASTIC HEMATOPOIETIC PROGENITORS

The t(8;21)-encoded AML1-ETO chimeric product is believed to be causal ly involved in up to 15% of acute myelogenous leukemias through an as yet unknown mechanism. To directly investigate the role of AMI.1-ETO i n leukemogenesis, we used gene targeting to create an AML1-ETO ''knock -in'' allele that mimics the t(8;21). Unexpectedly, embryos heterozygo us for AML1-ETO (AML1-ETO/+) died around E13.5 from a complete absence of normal fetal liver-derived definitive hematopoiesis and lethal hem orrhages. This phenotype was similar to that seen following homozygous disruption of either AML1 or CBF beta. However, in contrast to AML1- or CBF beta-deficient embryos, fetal livers from AML1-ETO/+ embryos co ntained dysplastic multilineage hematopoietic progenitors that had an abnormally high self-renewal capacity in vitro. To further document th e role of AML1 ETO in these growth abnormalities, we used retroviral t ransduction to express AML1-ETO in murine adult bone marrow-derived he matopoietic progenitors. AML1 ETO-expressing cells were again found to have an increased self-renewal capacity and could be readily establis hed into immortalized sell lines in vitro. Taken together, these studi es suggest that AML1-ETO not only neutralizes the normal biologic acti vity of AML1 but also directly induces aberrant hematopoietic cell pro liferation. (C) 1998 by The American Society of Hematology.