AML1, THE TARGET OF MULTIPLE CHROMOSOMAL TRANSLOCATIONS IN HUMAN LEUKEMIA, IS ESSENTIAL FOR NORMAL FETAL LIVER HEMATOPOIESIS

The AML1-CBF beta transcription factor is the most frequent target of chromosomal rearrangements in human leukemia. To investigate its norma l function, we generated mice lacking AML1. Embryos with homozygous mu tations in AML1 showed normal morphogenesis and yolk sac-derived eryth ropoiesis, but lacked fetal liver hematopoiesis and died around E12.5. Sequentially targeted AML1(-/-) ES cells retained their capacity to d ifferentiate into primitive erythroid cells in vitro; however, no myel oid or erythroid progenitors of definitive hematopoietic origin were d etected in either the yolk sac or fetal livers of mutant embryos. More over, this hematopoietic defect was intrinsic to the stem cells in tha t AML1(-/-) ES cells failed to contribute to hematopoiesis in chimeric animals. These results suggest that AML1-regulated target genes are e ssential for definitive hematopoiesis of all lineages.