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Recurrent somatic mutations of the epigenetic modifier and tumor suppressor ASXL1 are common in myeloid malignancies, including chronic myeloid leukemia (CML), and are associated with poor clinical outcome. CRISPR/Cas9 has recently emerged as a powerful and versatile genome editing tool for genome engineering in various species. We have used the CRISPR/Cas9 system to correct the ASXL1 homozygous nonsense mutation present in the CML cell line KBM5, which lacks ASXL1 protein expression. CRISPR/Cas9-mediated ASXL1 homozygous correction resulted in protein re-expression with restored normal function, including down-regulation of Polycomb repressive complex 2 target genes. Significantly reduced cell growth and increased myeloid differentiation were observed in ASXL1 mutation-corrected cells, providing new insights into the role of ASXL1 in human myeloid cell differentiation. Mice xenografted with mutation-corrected KBM5 cells showed significantly longer survival than uncorrected xenografts. These results show that the sole correction of a driver mutation in leukemia cells increases survival in vivo in mice. This study provides proof-of-concept for driver gene mutation correction via CRISPR/Cas9 technology in human leukemia cells and presents a strategy to illuminate the impact of oncogenic mutations on cellular function and survival.

Original publication




Journal article



Publication Date





44061 - 44071


ASXL1, CRISPR, chronic myeloid leukemia, mutation correction, tumor suppressor, Animals, Base Sequence, CRISPR-Associated Proteins, CRISPR-Cas Systems, Cell Differentiation, Cell Line, Tumor, Cell Proliferation, Clustered Regularly Interspaced Short Palindromic Repeats, Codon, Nonsense, Gene Expression Regulation, Leukemic, Genetic Predisposition to Disease, Heterografts, Homozygote, Humans, Interleukin Receptor Common gamma Subunit, Leukemia, Myelogenous, Chronic, BCR-ABL Positive, Mice, Inbred NOD, Mice, Knockout, Mice, SCID, Molecular Sequence Data, Neoplasm Transplantation, Phenotype, Polycomb Repressive Complex 2, Repressor Proteins, Time Factors, Tumor Suppressor Proteins, Ubiquitin Thiolesterase