The DOI matches its Crossref record; 30 of the 30 references it cites were found in a registry or an index.
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.
Overview
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“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]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
Cites
A Programmable Dual-RNA–Guided DNA Endonuclease in Adaptive Bacterial Immunity
Jinek, M., Chylinski, K., Fonfara, I., Hauer, M., Doudna, J. A., & Charpentier, E. (2012) · Science · doi:10.1126/science.1225829 · Cited by 17,116
Multiplex Genome Engineering Using CRISPR/Cas Systems
Cong, L., Ran, F. A., Cox, D., Lin, S., Barretto, R., Habib, N., Hsu, P. D., Wu, X., Jiang, W., Marraffini, L. A., et al. (2013) · Science · doi:10.1126/science.1231143 · Cited by 15,339
Identification of the transforming EML4–ALK fusion gene in non-small-cell lung cancer
Soda, M., Choi, Y. L., Enomoto, M., Takada, S., Yamashita, Y., Ishikawa, S., Fujiwara, S.-I., Watanabe, H., Kurashina, K., Hatanaka, H., et al. (2007) · Nature · doi:10.1038/nature05945 · Cited by 5,439
Anaplastic Lymphoma Kinase Inhibition in Non–Small-Cell Lung Cancer
Kwak, E. L., Bang, Y., Camidge, D. R., Shaw, A. T., Solomon, B., Maki, R. G., Ou, S. I., Dezube, B. J., Janne, P. A., Costa, D. B., et al. (2010) · New England Journal of Medicine · doi:10.1056/nejmoa1006448 · Cited by 4,477
Modes of resistance to anti-angiogenic therapy
Bergers, G., & Hanahan, D. (2008) · Nature Reviews Cancer · doi:10.1038/nrc2442 · Cited by 2,953
CRISPR/Cas, the Immune System of Bacteria and Archaea
Horvath, P., & Barrangou, R. (2010) · Science · doi:10.1126/science.1179555 · Cited by 2,471
Fusion of a Kinase Gene, ALK , to a Nucleolar Protein Gene, NPM , in Non-Hodgkin's Lymphoma
Morris, S. W., Kirstein, M. N., Valentine, M. B., Dittmer, K., Shapiro, D. N., Saltman, D. L., & Look, A. T. (1994) · Science · doi:10.1126/science.8122112 · Cited by 2,428
Analysis of lung tumor initiation and progression using conditional expression of oncogenic K-rasPreprint
Jackson, E. L., Willis, N. A., Mercer, K. L., Bronson, R. T., Crowley, D. G., Montoya, R., Jacks, T., & Tuveson, D. A. (2001) · Genes & Development · doi:10.1101/gad.943001 · Cited by 1,927
The anaplastic lymphoma kinase in the pathogenesis of cancer
Chiarle, R., Voena, C., Ambrogio, C., Piva, R., & Inghirami, G. (2007) · Nature reviews. Cancer · doi:10.1038/nrc2291 · Cited by 896
Conditional mouse lung cancer models using adenoviral or lentiviral delivery of Cre recombinase
DuPage, M. J. P., Dooley, A. L., & Jacks, T. (2009) · Nature Protocols · doi:10.1038/nprot.2009.95 · Cited by 873
Cited by
Sorted by citations
Genome editing with CRISPR–Cas nucleases, base editors, transposases and prime editors
Anzalone, A. V., Koblan, L. W., & Liu, D. R. (2020) · Nature Biotechnology · doi:10.1038/s41587-020-0561-9 · Cited by 2,237
CRISPR-engineered T cells in patients with refractory cancer
Stadtmauer, E. A., Fraietta, J. A., Davis, M. M., Cohen, A. D., Weber, K. L., Lancaster, E., Mangan, P. A., Kulikovskaya, I., Gupta, M., Chen, F., et al. (2020) · Science · doi:10.1126/science.aba7365 · Cited by 1,478
The next generation of CRISPR–Cas technologies and applications
Pickar-Oliver, A., & Gersbach, C. A. (2019) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-019-0131-5 · Cited by 1,459
Delivering CRISPR: a review of the challenges and approaches
Lino, C. A., Harper, J. C., Carney, J. P., & Timlin, J. A. (2018) · Drug Delivery · doi:10.1080/10717544.2018.1474964 · Cited by 1,185
The promise and challenge of therapeutic genome editing
Doudna, J. A. (2020) · Nature · doi:10.1038/s41586-020-1978-5 · Cited by 1,126
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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
