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
Date
10/13/2004Pubmed ID
15477599Pubmed Central ID
PMC524043DOI
10.1073/pnas.0400751101Scopus ID
2-s2.0-6344282193 (requires institutional sign-in at Scopus site) 79 CitationsAbstract
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.
Author List
Fenske TS, Pengue G, Mathews V, Hanson PT, Hamm SE, Riaz N, Graubert TAAuthor
Timothy Fenske MD Professor in the Medicine department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AnimalsBase Sequence
Cell Survival
Colony-Forming Units Assay
Core Binding Factor Alpha 2 Subunit
DNA
Disease Models, Animal
Female
Gene Targeting
Hematopoietic Stem Cells
Humans
In Vitro Techniques
Male
Mice
Mice, Mutant Strains
Mice, Transgenic
Myeloproliferative Disorders
Oncogene Proteins, Fusion
Phenotype
RUNX1 Translocation Partner 1 Protein
Transcription Factors
Translocation, Genetic
