Expression of a conditional AML1-ETO oncogene bypasses embryonic lethality and establishes a murine model of human t(8;21) acute myeloid leukemia.
The AML1/CBFbeta transcription factor complex, a frequent target of chromosomal translocations in leukemia, is essential for the generation of definitive hematopoietic stem cells. Paradoxically, expression of the acute myeloid leukemia-associated AML1-ETO fusion protein in mice results not in leukemia, but in embryonic lethality due to an absence of normal hematopoiesis. To bypass the embryonic lethality, we generated a mouse strain with a conditional AML1-ETO knockin allele that contains a loxP bracketed transcriptional stop cassette 5' to the AML1-ETO fusion site. Activation of this allele in vivo by Cre-mediated recombination resulted in an enhanced replating efficiency of myeloid progenitors, but it did not block their differentiation, nor was it sufficient to induce leukemia. However, induction of cooperating mutations resulted in the development of an acute myeloid disease that mimicked many of the features of human AML1-ETO-expressing leukemia.
Higuchi
Masakazu
M
Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
O'Brien
Darin
D
Kumaravelu
Parasakthy
P
Lenny
Noel
N
Yeoh
Eng-Juh
EJ
Downing
James R
JR
D000208:Acute Disease; D000818:Animals; D018797:Cell Cycle Proteins / Q000378:metabolism; D002455:Cell Division / Q000235:genetics; D002891:Chromosomes, Human, Pair 21 / Q000235:genetics*; D002898:Chromosomes, Human, Pair 8 / Q000235:genetics*; D050676:Core Binding Factor Alpha 2 Subunit; D016207:Cytokines / Q000378:metabolism; D017931:DNA Primers / Q000737:chemistry; D004268:DNA-Binding Proteins / Q000502:physiology; D004195:Disease Models, Animal; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D019426:Integrases / Q000378:metabolism; D007951:Leukemia, Myeloid / Q000209:etiology* / Q000235:genetics* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D015514:Oncogene Proteins, Fusion / Q000235:genetics* / Q000378:metabolism; D011518:Proto-Oncogene Proteins; D000075142:RUNX1 Translocation Partner 1 Protein; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D014178:Translocation, Genetic / Q000235:genetics*; D014764:Viral Proteins / Q000378:metabolism
C107844:AML1-ETO fusion protein, human; D018797:Cell Cycle Proteins; D050676:Core Binding Factor Alpha 2 Subunit; D016207:Cytokines; D017931:DNA Primers; D004268:DNA-Binding Proteins; D015514:Oncogene Proteins, Fusion; D011518:Proto-Oncogene Proteins; D000075142:RUNX1 Translocation Partner 1 Protein; C493728:RUNX1 protein, human; C493726:Runx1 protein, mouse; D014157:Transcription Factors; D014764:Viral Proteins; C045073:Cre recombinase; D019426:Integrases