Chromosomal Translocation Engineering to Recapitulate Primary Events of Human Cancer

Abstract

Mouse models of human cancers are important for understanding determinants of overt disease and for "preclinical" developmentof rational therapeutic strategies; for instance, based on macrodrugs. Chromosomal translocations underlie many humanleukemias, sarcomas, and epithelial tumors. We have developed three technologies based on homologous recombinationin mouse ES cells to mimic human chromosome translocations. The first, called the knockin method, allows creation offusion genes like those typical of translocations of human leukemias and sarcomas. Two new conditional chromosomaltranslocation mimics have been developed. The first is a method for generating reciprocal chromosomal translocations denovo using Cre-loxP recombination (translocator mice). In some cases, there is incompatible gene orientation and the translocatormodel cannot be applied. We have developed a different model (invertor mice) for these situations. This method consistsof introducing an inverted cDNA cassette into the intron of a target gene and bringing the cassette into the correct transcriptionalorientation by Cre-loxP recombination. We describe experiments using the translocator model to generateMLL-mediated neoplasias and the invertor method to generate EWS-ERG-mediated cancer. These methods mimic the situationfound in human chromosome translocations and provide the framework for design and study of human chromosomaltranslocations in mice.