EMBRYONIC LETHALITY AND IMPAIRMENT OF HEMATOPOIESIS IN MICE HETEROZYGOUS FOR AN AML1-ETO FUSION GENE

Acute myeloid leukaemia (AML) is a major haematopoietic malignancy cha racterized by the proliferation of a malignant clone of myeloid progen itor cells(1,2). A reciprocal translocation, t(8;21)(q22;q22), observe d in the leukaemic cells of approximately 40% of patients with the M2 subtype of AML disrupts both the AML1 (CBFA2) gene on chromosome 21 an d the ETO (MTG8) gene on chromosome 8 (refs 3-5). A chimaeric protein is synthesized from one of the derivative chromosomes that contains th e N terminus of the AML1 transcription factor, including its DNA-bindi ng domain, fused to most of ETO, a protein of unknown function. We gen erated mice that mimic human t(8;21) with a 'knock-in' strategy. Mice heterozygous for an AML I-ETO allele (AML1-ETO/+) die in midgestation from haemorrhaging in the central nervous system and exhibit a severe block in fetal liver haematopoiesis. This phenotype is very similar to that resulting from homozygous disruption of the AML1 (Cbfa2) or Cbfb genes(6-8), indicating that AML1-ETO blocks normal AML1 function. How ever, yolk sac cells from AML1-ETO/+ mice differentiated into macropha ges in haematopoietic colony forming unit (CFU) assays, unlike Cbfa2-/ - or Cbfb-/- cells, which form no colonies in vitro(6-8). This indicat es that AML1-ETO may have other functions besides blocking wild-type A ML1, a property that may be important in leukaemogenesis.