Embryonic lethality and impairment of haematopoiesis in mice heterozygous for an AML1-ETO fusion gene

Nat Genet. 1997 Mar;15(3):303-6. doi: 10.1038/ng0397-303.


Acute myeloid leukaemia (AML) is a major haematopoietic malignancy characterized by the proliferation of a malignant clone of myeloid progenitor cells. A reciprocal translocation, t(8;21)(q22;q22), observed in the leukaemic cells of approximately 40% of patients with the M2 subtype of AML disrupts both the AML1 (CBFA2) gene on chromosome 21 and the ETO (MTG8) gene on chromosome 8 (refs 3-5). A chimaeric protein is synthesized from one of the derivative chromosomes that contains the N terminus of the AML1 transcription factor, including its DNA-binding domain, fused to most of ETO, a protein of unknown function. We generated mice that mimic human t(8;21) with a "knock-in' strategy. Mice heterozygous for an AML1-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, indicating that AML1-ETO blocks normal AML1 function. However, yolk sac cells from AML1-ETO/+ mice differentiated into macrophages in haematopoietic colony forming unit (CFU) assays, unlike Cbfa2-/- or Cbfb-/-cells, which form no colonies in vitro. This indicates that AML1-ETO may have other functions besides blocking wild-type AML1, a property that may be important in leukaemogenesis.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Chimera
  • Chromosome Mapping
  • Chromosomes, Human, Pair 21
  • Chromosomes, Human, Pair 8
  • Cloning, Molecular*
  • Core Binding Factor Alpha 2 Subunit
  • Crosses, Genetic
  • DNA-Binding Proteins / biosynthesis
  • DNA-Binding Proteins / genetics*
  • Exons
  • Female
  • Fetal Death / genetics*
  • Genetic Carrier Screening
  • Hematopoiesis / genetics*
  • Humans
  • Leukemia, Myeloid / genetics
  • Liver / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Mutant Strains
  • Proto-Oncogene Proteins*
  • RUNX1 Translocation Partner 1 Protein
  • Transcription Factors / biosynthesis
  • Transcription Factors / genetics*
  • Translocation, Genetic
  • Yolk Sac


  • Core Binding Factor Alpha 2 Subunit
  • DNA-Binding Proteins
  • Proto-Oncogene Proteins
  • RUNX1 Translocation Partner 1 Protein
  • RUNX1 protein, human
  • RUNX1T1 protein, human
  • Runx1 protein, mouse
  • Transcription Factors