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In vivo engineering of oncogenic chromosomal rearrangements with the CRISPR/Cas9 system
Open accessAbstract
Chromosomal rearrangements have a central role in the pathogenesis of human cancers and often result in the expression of therapeutically actionable gene fusions. 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). The EML4-ALK oncogene is detected in a subset of human non-small cell lung cancers (NSCLC) and is clinically relevant because it confers sensitivity to ALK inhibitors. 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 mouse model of Eml4-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 ALK(+) 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.
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“Although these events occur at low frequency, they could be significant in a clinical setting if rare translocations led to cancer 97-99 .”
From The promise and challenge of therapeutic genome editing (2020) · cites this paper as [98]
Experimental — accuracy not yet measuredIn the citing paper
“In addition, CRISPR/Cas9 system has shown potentials in polygenetic diseases, such as cancer, by inhibiting oncogene expression or deactivating oncogenic virus [52–55].”
From Non-viral delivery systems for CRISPR/Cas9-based genome editing: challenges and opportunities (2018) · cites this paper as [55]
In the citing paper
“To establish disease models, in 2014, Maddalo et al. generated a model of non-small cell lung cancer by creating an Eml4 and Alk fusion gene through the intratracheal instillation of AdV-delivered CRISPR/Cas9 [35].”
From Viral Delivery Systems for CRISPR (2019) · cites this paper as [35]
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Metadata
- 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.
- Affiliations
- Memorial Sloan Kettering Cancer Center (US)
- Azienda Ospedaliera San Gerardo (IT)
- Corresponding author
- Ventura, Andrea
- ORCID
- Venue
- Nature
- Published
- 2014-10-22
- Volume
- 516
- Issue
- 7531
- Pages
- 423-427
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC4270925
- OpenAlex
- W1972759536
- Cited by
- 640
- References
- 30
- Citations by year
- 2026: 21 · 2025: 29 · 2024: 43 · 2023: 45 · 2022: 61 · 2021: 53 · 2020: 53 · 2019: 55 · 2018: 68 · 2017: 65 · 2016: 81 · 2015: 63 · 2014: 2
- FWCI
- 28.86
- Type
- journal article
- Language
- en
- Update notices
- correction (2015-06-24)
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- Howard Hughes Medical Institute
- Memorial Sloan-Kettering Cancer Center
- National Institutes of Health
- National Cancer Institute (P01CA129243, P01CA013106, P30CA008748)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › CRISPR and Genetic Engineering
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
- Keywords
- EML4-ALK fusion, chromosomal rearrangements, non-small cell lung cancer, somatic genome editing, tumor suppressor, oncogene cooperation
- MeSH terms
- Crizotinib, Anaplastic Lymphoma Kinase, Animals, Antineoplastic Agents, Cells, Cultured, Disease Models, Animal, Genetic Engineering, Chromosome Inversion, Lung Neoplasms, Pyrazoles, Pyridines, Translocation, Genetic, Receptor Protein-Tyrosine Kinases, NIH 3T3 Cells, Protein Kinase Inhibitors, Mice, Clustered Regularly Interspaced Short Palindromic Repeats, CRISPR-Cas Systems, CRISPR-Associated Proteins
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