Expression of a knocked-in AML1-ETO leukemia gene inhibits the establishment of normal definitive hematopoiesis and directly generates dysplastic hematopoietic progenitors.

摘要: The t(8;21)-encoded AML1-ETO chimeric product is believed to be causally involved in up 15% of acute myelogenous leukemias through an as yet unknown mechanism. To directly investigate the role leukemogenesis, we used gene targeting create "knock-in" allele that mimics t(8;21). Unexpectedly, embryos heterozygous for (AML1-ETO/+) died around E13.5 from a complete absence normal fetal liver-derived definitive hematopoiesis and lethal hemorrhages. This phenotype was similar seen following homozygous disruption either AML1 or CBFbeta. However, contrast AML1- CBFbeta-deficient embryos, livers AML1-ETO/+ contained dysplastic multilineage hematopoietic progenitors had abnormally high self-renewal capacity vitro. further document these growth abnormalities, retroviral transduction express murine adult bone marrow-derived progenitors. AML1-ETO-expressing cells were again found have increased could readily established into immortalized cell lines Taken together, studies suggest not only neutralizes biologic activity but also induces aberrant proliferation.