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- Title
Generation of mouse models of myeloid malignancy with combinatorial genetic lesions using CRISPR-Cas9 genome editing.
- Authors
Heckl, Dirk; Kowalczyk, Monika S; Yudovich, David; Belizaire, Roger; Puram, Rishi V; McConkey, Marie E; Thielke, Anne; Aster, Jon C; Regev, Aviv; Ebert, Benjamin L
- Abstract
Genome sequencing studies have shown that human malignancies often bear mutations in four or more driver genes, 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 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.
- Subjects
MYELOID leukemia; HEMATOPOIETIC stem cells; GENETIC mutation; TRANSCRIPTION factors; CELLULAR signal transduction; LABORATORY mice; NON-coding RNA; PATIENTS
- Publication
Nature Biotechnology, 2014, Vol 32, Issue 9, p941
- ISSN
1087-0156
- Publication type
Article
- DOI
10.1038/nbt.2951