Generation of mouse models of myeloid malignancy with combinatorial genetic lesions using CRISPR-Cas9 genome editing.

Nat Biotechnol
Authors
Keywords
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.

Year of Publication
2014
Journal
Nat Biotechnol
Volume
32
Issue
9
Pages
941-6
Date Published
2014 Sep
ISSN
1546-1696
URL
DOI
10.1038/nbt.2951
PubMed ID
24952903
PubMed Central ID
PMC4160386
Links
Grant list
R01 HL082945 / HL / NHLBI NIH HHS / United States
T32 GM007753 / GM / NIGMS NIH HHS / United States
P01 CA066996 / CA / NCI NIH HHS / United States
P01 CA108631 / CA / NCI NIH HHS / United States
P50 HG006193 / HG / NHGRI NIH HHS / United States
5P50HG006193-02 / HG / NHGRI NIH HHS / United States