In vivo engineering of oncogenic chromosomal rearrangements with the CRISPR/Cas9 system Journal Article

Authors: Maddalo, D.; Manchado, E.; Concepcion, C. P.; Bonetti, C.; Vidigal, J. A.; Han, Y. C.; Ogrodowski, P.; Crippa, A.; Rekhtman, N.; de Stanchina, E.; Lowe, S. W.; Ventura, A.
Article Title: In vivo engineering of oncogenic chromosomal rearrangements with the CRISPR/Cas9 system
Abstract: Chromosomal rearrangements have a central role in the pathogenesis of human cancers and often result in the expression of therapeutically actionable gene fusions1. A recently discovered example is a fusion between the genes echinoderm microtubule-associated protein like 4 (EML4) and anaplastic lymphoma kinase (ALK), generated by an inversion on the short arm of chromosome 2: inv(2) (p21p23).TheEML4-ALK oncogene is detected in a subset of human non-small cell lung cancers (NSCLC)2 and is clinically relevant because it confers sensitivity to ALK inhibitors3. Despite their importance, modelling such genetic events in mice has proven challenging and requires complex manipulation of the germ line. Here we describe an efficient method to induce specific chromosomal rearrangements in vivo using viral-mediated delivery of the CRISPR/Cas9 system to somatic cells of adult animals. We apply it to generate a mousemodel ofEml4-Alk-driven lung cancer.The resulting tumours invariably harbour the Eml4-Alk inversion, express the Eml4-Alk fusion gene, display histopathological and molecular features typical of ALK1 human NSCLCs, and respond to treatment with ALK inhibitors.The general strategy described here substantially expands our ability to model human cancers in mice and potentially in other organisms.
Keywords: nonhuman; mus; somatic cell; reverse transcription polymerase chain reaction; intron; lung cancer; in vivo study; animalia; dna strand breakage; oncogene; genetic engineering; fusion gene; chromosome rearrangement; chromosome translocation; double stranded dna break; caspase 9; micro-computed tomography; eukaryotic cell; loss of function mutation; chromosome 17; anaplastic lymphoma kinase; human; priority journal; article; clustered regularly interspaced short palindromic repeat; microtubule associated protein 4; 3t3 cell line; echinodermata
Journal Title: Nature
Volume: 516
Issue: 7531
ISSN: 0028-0836
Publisher: Nature Publishing Group  
Date Published: 2014-12-18
Start Page: 423
End Page: 428
Language: English
DOI: 10.1038/nature13902
PROVIDER: scopus
PMCID: PMC4270925
PUBMED: 25337876
Notes: Export Date: 2 March 2015 -- Source: Scopus
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