Stem cell expression of the AML1/ETO fusion protein induces a myeloproliferative disorder in mice.
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.
Stem Cell Biology Section, Division of Oncology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
Timothy S
TS
Fenske
Gina
G
Pengue
Vikram
V
Mathews
Piia T
PT
Hanson
Sarah E
SE
Hamm
Noor
N
Riaz
Timothy A
TA
Graubert
D000818:Animals; D001483:Base Sequence; D002470:Cell Survival; D003114:Colony-Forming Units Assay; D050676:Core Binding Factor Alpha 2 Subunit; D004247:DNA / Q000235:genetics; D004195:Disease Models, Animal; D005260:Female; D018390:Gene Targeting; D006412:Hematopoietic Stem Cells / Q000378:metabolism*; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D009196:Myeloproliferative Disorders / Q000209:etiology* / Q000235:genetics / Q000473:pathology; D015514:Oncogene Proteins, Fusion / Q000235:genetics* / Q000502:physiology*; D010641:Phenotype; D000075142:RUNX1 Translocation Partner 1 Protein; D014157:Transcription Factors / Q000235:genetics* / Q000502:physiology*; D014178:Translocation, Genetic
C107844:AML1-ETO fusion protein, human; D050676:Core Binding Factor Alpha 2 Subunit; D015514:Oncogene Proteins, Fusion; D000075142:RUNX1 Translocation Partner 1 Protein; D014157:Transcription Factors; D004247:DNA