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.
Fenske
Timothy S
TS
Stem Cell Biology Section, Division of Oncology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
Pengue
Gina
G
Mathews
Vikram
V
Hanson
Piia T
PT
Hamm
Sarah E
SE
Riaz
Noor
N
Graubert
Timothy A
TA
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