An Mll-AF9 fusion gene made by homologous recombination causes acute leukemia in chimeric mice: a method to create fusion oncogenes.
Homologous recombination in embryonal stem cells has been used to produce a fusion oncogene, thereby mimicking chromosomal translocations that frequently result in formation of tumor-specific fusion oncogenes in human malignancies. AF9 sequences were fused into the mouse Mll gene so that expression of the Mll-AF9 fusion gene occurred from endogenous Mll transcription control elements, as in t(9;11) found in human leukemias. Chimeric mice carrying the fusion gene developed tumors, which were restricted to acute myeloid leukemias despite the widespread activity of the Mll promoter. Onset of perceptible disease was preceded by expansion of ES cell derivatives in peripheral blood. This novel use of homologous recombination formally proves that chromosomal translocations contribute to malignancy and provides a general strategy to create fusion oncogenes for studying their role in tumorigenesis.
Corral
J
J
Medical Research Council Laboratory of Molecular Biology, Cambridge, United Kingdom.
Lavenir
I
I
Impey
H
H
Warren
A J
AJ
Forster
A
A
Larson
T A
TA
Bell
S
S
McKenzie
A N
AN
King
G
G
Rabbitts
T H
TH
D000208:Acute Disease; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002678:Chimera; D004274:DNA, Recombinant; D004268:DNA-Binding Proteins / Q000235:genetics*; D018390:Gene Targeting; D011495:Histone-Lysine N-Methyltransferase; D006801:Humans; D007942:Leukemia, Experimental / Q000235:genetics*; D007951:Leukemia, Myeloid / Q000097:blood / Q000473:pathology; D051379:Mice; D008969:Molecular Sequence Data; D051788:Myeloid-Lymphoid Leukemia Protein; D009687:Nuclear Proteins / Q000235:genetics*; D009857:Oncogenes / Q000235:genetics*; D011519:Proto-Oncogenes; D011993:Recombinant Fusion Proteins / Q000032:analysis; D011995:Recombination, Genetic; D013154:Spleen / Q000737:chemistry; D013234:Stem Cells; D013950:Thymus Gland / Q000737:chemistry; D014157:Transcription Factors; D014178:Translocation, Genetic / Q000235:genetics
D004274:DNA, Recombinant; D004268:DNA-Binding Proteins; C497422:KMT2A protein, human; C489901:MLLT3 protein, human; C489902:Mllt3 protein, mouse; D009687:Nuclear Proteins; D011993:Recombinant Fusion Proteins; D014157:Transcription Factors; D051788:Myeloid-Lymphoid Leukemia Protein; D011495:Histone-Lysine N-Methyltransferase; C497423:Kmt2a protein, mouse