Sequential gene targeting to make chimeric tumor models with de novo chromosomal abnormalities.
Cancer Res
; 74(5): 1588-97, 2014 Mar 01.
Article
en En
| MEDLINE
| ID: mdl-24419086
ABSTRACT
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.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Translocación Genética
/
Proteínas de Fusión Oncogénica
/
Marcación de Gen
/
Neoplasias
Límite:
Animals
/
Humans
Idioma:
En
Revista:
Cancer Res
Año:
2014
Tipo del documento:
Article
País de afiliación:
España