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

Abstract

Acute myeloid leukaemia (AMI) is a major haematopoietic malignancy characterized by the proliferation of a malignant clone of myeloid progenitor cells1,2. A reciprocal translocation, t(8;21)(q22;q22), observed in the leukaemic cells of approximately 40% of patients with the M2 subtype of AMI 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 DMA-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 genes6–8, indicating that AML1-ETO blocks normal AML1 function. However, yolk sac cells from AMU-ETO/+ mice differentiated into macrophages in haematopoietic colony forming unit (CPU) assays, unlike Cbfa2−/− or Cbfb−/− cells, which form no colonies in vitro6,8. This indicates that AML1–ETO may have other functions besides blocking wild-type AML1, a property that may be important in leukaemogenesis.

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Correspondence to Dong-Er Zhang.

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Yergeau, D., Hetherington, C., Wang, Q. et al. Embryonic lethality and impairment of haematopoiesis in mice heterozygous for an AML1-ETO fusion gene. Nat Genet 15, 303–306 (1997). https://doi.org/10.1038/ng0397-303

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