Development and Applications of CRISPR-KO screening遊佐 宏介1) Koike-Yusa H, Li Y, Tan EP, et al. Genome-wide recessive genetic screening in mammalian cells with a lentivial CRISPR-guide RNA library. Nat Biotechnol. 2014. 32(3):267-273.2) Behan FM, Iorio F, Picco G, et al. Prioritisation of oncology therapeutic targets using CRISPR-Cas9 screening. Nature. 2019. 568(7753):511-516.3) Aoki K, Hyuga M, Tarumoto Y, et al. Canonical BAF complex regulates the oncogenic program in human T-cell acute lymphoblastic leukemia. Blood. 2024. 143(7):604-618.京都大学 医生物学研究所 幹細胞遺伝学分野5. CRISPR-KO スクリーニングの開発と応用The advent of the CRISPR system has transformed the landscape of genetic studies. Its high efficiency, simplicity and scalability have enabled us to develop a number of genome engineering tools, some of which have already been approved or actively tested in clinical applications. One of our group’s focuses is to develop forward genetics tools for large-scale functional genomics. Applying the CRIPSR-Cas9 technology, we developed genome-scale CRISPR knockout screening1, which has now been used in various biological research. As one of applications, we systematically characterized genetic dependencies in cancer cells. We screened a panel of 324 cancer cell lines and proposed more than 600 high-priority targets for drug development2, from which WRN was identified a novel synthetic lethal partner with microsatellite instability. Our most recent screen focused on T-cell acute lymphoblastic leukemia and identified SWI/SNF chromatin remodeling factors, which are essential to maintain the RUNX1-dependent leukemia transcriptional program3. SWI/SNF inhibitors suppressed leukemic cell proliferation in vitro and in vivo, suggesting that it would be worth exploring further as a novel therapeutic strategy. CRISPR screens can also be used to identify modulators of drug sensitivity. This approach enables us to investigate possibilities of drug combination or biomarker identification. Laboratory of Stem Cell Genetics, Institute for Life and Medical Sciences, Kyoto University Kosuke Yusa11
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