Generation of mouse models of myeloid malignancy with combinatorial genetic lesions using CRISPR-Cas9 genome editing
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Author(s)
Heckl, Dirk
Kowalczyk, Monika S.
Yudovich, David
Belizaire, Roger
Puram, Rishi V.
McConkey, Marie
Thielke, Anne
Aster, Jon C.
Regev, Aviv
Ebert, Benjamin L.
Date Issued
June 2014
Journal
Nature Biotechnology
Publisher
Nature Publishing Group
Citation
Heckl, Dirk, Monika S Kowalczyk, David Yudovich, Roger Belizaire, Rishi V Puram, Marie E McConkey, Anne Thielke, Jon C Aster, Aviv Regev, and Benjamin L Ebert. “Generation of Mouse Models of Myeloid Malignancy with Combinatorial Genetic Lesions Using CRISPR-Cas9 Genome Editing.” Nature Biotechnology 32, no. 9 (June 22, 2014): 941–946.
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Author's final manuscript
Abstract
Genome sequencing studies have shown that human malignancies often bear mutations in four or more driver genes[superscript 1], but it is difficult to recapitulate this degree of genetic complexity in mouse models using conventional breeding. Here we use the CRISPR-Cas9 system of genome editing[superscript 2, 3, 4] to overcome this limitation. By delivering combinations of small guide RNAs (sgRNAs) and Cas9 with a lentiviral vector, we modified up to five genes in a single mouse hematopoietic stem cell (HSC), leading to clonal outgrowth and myeloid malignancy. We thereby generated models of acute myeloid leukemia (AML) with cooperating mutations in genes encoding epigenetic modifiers, transcription factors and mediators of cytokine signaling, recapitulating the combinations of mutations observed in patients. Our results suggest that lentivirus-delivered sgRNA:Cas9 genome editing should be useful to engineer a broad array of in vivo cancer models that better reflect the complexity of human disease.
MIT Department
Massachusetts Institute of Technology. Department of Biology
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DOI of Published Version
https://doi.org/10.1038/nbt.2951
