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

Chromosomal translocations and other abnormalities are central to the initiation of cancer in all cell types. Understanding the mechanism is therefore important to evaluate the evolution of cancer from the cancer initiating events to overt disease. Recent work has concentrated on model systems to develop an understanding of the molecular mechanisms of translocations but naturally occurring events are more ideal case studies since biological selection is absent from model systems. In solid tumours, nonreciprocal translocations are most commonly found, and accordingly we have investigated the recurrent nonreciprocal t(3;5) chromosomal translocations in renal carcinoma to better understand the mechanism of these naturally occurring translocations in cancer. Unexpectedly, the junctions of these translocations can be associated with site-specific, intrachromosomal inversion involving at least two double strand breaks (DSB) in cis and rejoining by nonhomologous end joining or micro-homology end joining. However, these translocations are not necessarily associated with transcribed regions questioning accessibility per se in controlling these events. In addition, intrachromosomal deletions also occur. We conclude these naturally occurring, nonreciprocal t(3;5) chromosomal translocations occur after complex and multiple unresolved intrachromosomal DSBs leading to aberrant joining with concurrent interstitial inversion and that clonal selection of cells is the critical element in cancer development emerging from a plethora of DSBs that may not always be pathogenic. V C 2013 Wiley Periodicals, Inc.