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

Blood. 1998 May 1;91(9):3134-43.


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

Publication types

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

MeSH terms

  • Animals
  • Bone Marrow Cells / pathology
  • Core Binding Factor Alpha 2 Subunit
  • DNA-Binding Proteins / genetics*
  • Gene Expression Regulation, Developmental
  • Genes, Lethal
  • Hematopoiesis*
  • Hematopoietic Stem Cells / cytology
  • Heterozygote
  • Leukemia, Myeloid, Acute / genetics*
  • Leukemia, Myeloid, Acute / pathology
  • Liver / embryology
  • Mice
  • Mice, Transgenic
  • Neoplasm Proteins / genetics
  • Proto-Oncogene Proteins*
  • RUNX1 Translocation Partner 1 Protein
  • Recombinant Fusion Proteins
  • Transcription Factors / genetics*
  • Yolk Sac / cytology


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