Stem cell expression of the AML1/ETO fusion protein induces a myeloproliferative disorder in mice

Proc Natl Acad Sci U S A. 2004 Oct 19;101(42):15184-9. doi: 10.1073/pnas.0400751101. Epub 2004 Oct 11.

Abstract

The t(8;21)(q22;q22) translocation, present in 10-15% of acute myeloid leukemia (AML) cases, generates the AML1/ETO fusion protein. To study the role of AML1/ETO in the pathogenesis of AML, we used the Ly6A locus that encodes the well characterized hematopoietic stem cell marker, Sca1, to target expression of AML1/ETO to the hematopoietic stem cell compartment in mice. Whereas germ-line expression of AML1/ETO from the AML1 promoter results in embryonic lethality, heterozygous Sca1(+/AML1-ETO ires EGFP) (abbreviated Sca(+/AE)) mutant mice are born in Mendelian ratios with no apparent abnormalities in growth or fertility. Hematopoietic cells from Sca(+/AE) mice have markedly extended survival in vitro and increasing myeloid clonogenic progenitor output over time. Sca(+/AE) mice develop a spontaneous myeloproliferative disorder with a latency of 6 months and a penetrance of 82% at 14 months. These results reinforce the notion that the phenotype of murine transgenic models of human leukemia is critically dependent on the cellular compartment targeted by the transgene. This model should provide a useful platform to analyze the effect of AML1/ETO on hematopoiesis and its potential cooperation with other mutations in the pathogenesis of leukemia.

Publication types

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

MeSH terms

  • Animals
  • Base Sequence
  • Cell Survival
  • Colony-Forming Units Assay
  • Core Binding Factor Alpha 2 Subunit
  • DNA / genetics
  • Disease Models, Animal
  • Female
  • Gene Targeting
  • Hematopoietic Stem Cells / metabolism*
  • Humans
  • In Vitro Techniques
  • Male
  • Mice
  • Mice, Mutant Strains
  • Mice, Transgenic
  • Myeloproliferative Disorders / etiology*
  • Myeloproliferative Disorders / genetics
  • Myeloproliferative Disorders / pathology
  • Oncogene Proteins, Fusion / genetics*
  • Oncogene Proteins, Fusion / physiology*
  • Phenotype
  • RUNX1 Translocation Partner 1 Protein
  • Transcription Factors / genetics*
  • Transcription Factors / physiology*
  • Translocation, Genetic

Substances

  • AML1-ETO fusion protein, human
  • Core Binding Factor Alpha 2 Subunit
  • Oncogene Proteins, Fusion
  • RUNX1 Translocation Partner 1 Protein
  • Transcription Factors
  • DNA