RNA-Guided CRISPR-Cas9 System-Mediated Engineering of Acute Myeloid Leukemia Mutations

Current acute myeloid leukemia (AML) disease models face severe limitations because most of them induce un-physiological gene expressions that do not represent conditions in AML patients and/or depend on external promoters for regulation of gene expression/repression. Furthermore, many AML models ar...

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Bibliographic Details
Published in:Molecular therapy. Nucleic acids 2017-03, Vol.6, p.243-248
Main Authors: Brabetz, Oliver, Alla, Vijay, Angenendt, Linus, Schliemann, Christoph, Berdel, Wolfgang E., Arteaga, Maria-Francisca, Mikesch, Jan-Henrik
Format: Article
Language:English
Subjects:
Acute myeloid leukemia
AML
Binding sites
Chromosome translocations
CRISPR
CRISPR-Cas9
Deoxyribonucleic acid
DNA
DNA methylation
Efficiency
Epigenetics
Experiments
Gene expression
genome editing
Genomes
Homologous recombination
Immunoglobulins
Karyotypes
Leukemia
Mutation
Myeloid leukemia
Original
Plasmids
Proteins
Ribonucleic acid
RNA
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Summary:Current acute myeloid leukemia (AML) disease models face severe limitations because most of them induce un-physiological gene expressions that do not represent conditions in AML patients and/or depend on external promoters for regulation of gene expression/repression. Furthermore, many AML models are based on reciprocal chromosomal translocations that only reflect the minority of AML patients, whereas more than 50% of patients have a normal karyotype. The majority of AML, however, is driven by somatic mutations. Thus, identification as well as a detailed molecular and functional characterization of the role of these driver mutations via improved AML models is required for better approaches toward novel targeted therapies. Using the IDH2 R140Q mutation as a model, we present a new effective methodology here using the RNA-guided clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 system to reproduce or remove AML-associated mutations in or from human leukemic cells, respectively, via introduction of a DNA template at the endogenous gene locus via homologous recombination. Our technology represents a precise way for AML modeling to gain insights into AML development and progression and provides a basis for future therapeutic approaches.
ISSN:2162-2531
2162-2531
DOI:10.1016/j.omtn.2016.12.012