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The discovery of chromosomal translocations in leukemia/lymphoma and sarcomas presaged a widespread discovery in epithelial tumors. With the advent of new-generation whole-genome sequencing, many consistent chromosomal abnormalities have been described together with putative driver and passenger mutations. The multiple genetic changes required in mouse models to assess the interrelationship of abnormalities and other mutations are severe limitations. Here, we show that sequential gene targeting of embryonic stem cells can be used to yield progenitor cells to generate chimeric offspring carrying all the genetic changes needed for cell-specific cancer. Illustrating the technology, we show that MLL-ENL fusion is sufficient for lethal leukocytosis and proof of genome integrity comes from germline transmission of the sequentially targeted alleles. This accelerated technology leads to a reduction in mouse numbers (contributing significantly to the 3Rs), allows fluorescence tagging of cancer-initiating cells, and provides a flexible platform for interrogating the interaction of chromosomal abnormalities with mutations.

Original publication

DOI

10.1158/0008-5472.CAN-13-1783

Type

Journal article

Journal

Cancer Res

Publication Date

01/03/2014

Volume

74

Pages

1588 - 1597

Keywords

Alleles, Amino Acid Sequence, Animals, Base Sequence, Chromosome Aberrations, Embryonic Stem Cells, Gene Targeting, Humans, Leukocytosis, Mice, Molecular Sequence Data, Mutation, Neoplasms, Oncogene Proteins, Fusion, Stem Cells, Translocation, Genetic