Engineering de novo reciprocal chromosomal translocations associated with Mll to replicate primary events of human cancer.
The etiology of human tumors often involves chromosomal translocations. Models that emulate translocations are essential to understanding the determinants of frank malignancy, those dictating the restriction of translocations to specific lineages, and as a basis for development of rational therapeutic methods. We demonstrate that developmentally regulated Cre-loxP-mediated interchromosomal recombination between the Mll gene, whose human counterpart is involved in a spectrum of leukemias, and the Enl gene creates reciprocal chromosomal translocations that cause myeloid tumors. There is a rapid onset and high penetrance of leukemogenesis in these translocator mice, and high proportions of cells carrying chromosomal translocations can be found in bone marrow as early as 12 days after birth. This de novo strategy is a direct recapitulation of naturally occurring human cancer-associated translocations.
Forster
Alan
A
MRC Laboratory of Molecular Biology, Cambridge, United Kingdom.
Pannell
Richard
R
Drynan
Lesley F
LF
McCormack
Matthew
M
Collins
Emma C
EC
Daser
Angelika
A
Rabbitts
Terence H
TH
D000483:Alleles; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002875:Chromosomes / Q000648:ultrastructure*; D004268:DNA-Binding Proteins / Q000235:genetics*; D004195:Disease Models, Animal; D005434:Flow Cytometry; D005821:Genetic Techniques; D005838:Genotype; D011495:Histone-Lysine N-Methyltransferase; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D007962:Leukocytes / Q000378:metabolism; D051379:Mice; D008957:Models, Genetic; D008969:Molecular Sequence Data; D051788:Myeloid-Lymphoid Leukemia Protein; D009369:Neoplasms / Q000235:genetics*; D015514:Oncogene Proteins, Fusion / Q000235:genetics*; D010641:Phenotype; D011519:Proto-Oncogenes; D011995:Recombination, Genetic; D013997:Time Factors; D014157:Transcription Factors; D014178:Translocation, Genetic
D004268:DNA-Binding Proteins; C497422:KMT2A protein, human; C425207:MLL-ENL oncoprotein, human; D015514:Oncogene Proteins, Fusion; D014157:Transcription Factors; D051788:Myeloid-Lymphoid Leukemia Protein; D011495:Histone-Lysine N-Methyltransferase; C497423:Kmt2a protein, mouse