A CRISPR Dropout Screen Identifies Genetic Vulnerabilities and Therapeutic Targets in Acute Myeloid Leukemia

By K. Tzelepis, Hiroko Koike-Yusa, E. De Braekeleer, Yilong Li, E. Metzakopian, O. Dovey, Annalisa Mupo, V. Grinkevich, M. Li, M. Mazan and 17 more. Cell Reports, 2016

609 citations recorded by the source corpus.

Summary Acute myeloid leukemia (AML) is an aggressive cancer with a poor prognosis, for which mainstream treatments have not changed for decades. To identify additional therapeutic targets in AML, we optimize a genome-wide clustered regularly interspaced short palindromic repeats (CRISPR) screening platform and use it to identify genetic vulnerabilities in AML cells. We identify 492 AML-specific cell-essential genes, including several established therapeutic targets such as DOT1L, BCL2, and MEN1, and many other genes including clinically actionable candidates. We validate selected genes using genetic and pharmacological inhibition, and chose KAT2A as a candidate for downstream study. KAT2A inhibition demonstrated anti-AML activity by inducing myeloid differentiation and apoptosis, and suppressed the growth of primary human AMLs of diverse genotypes while sparing normal hemopoietic stem-progenitor cells. Our results propose that KAT2A inhibition should be investigated as a therapeutic strategy in AML and provide a large number of genetic vulnerabilities of this leukemia that can be pursued in downstream studies.

Subfields: Hematology, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/9ae43503651eb016905998c9c8fc5228f9d1a404

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In Molecular Biology

Citations in the corpus

Evaluation and Design of Genome-Wide CRISPR/SpCas9 Knockout Screens (2017, methodology): “With several panels of whole-genome cell-line screens published (Aguirre et al. 2016; Hart et al. 2015; Tzelepis et al. 2016; Wang et al. 2015, 2017), the opportunity now exists to undertake a meta-analysis as a means to uncover the drivers of screen quality and variability.”
Applications of genome editing technology in the targeted therapy of human diseases: mechanisms, advances and prospects (2020, background): “One of the chief goals of pooled CRISPR/Cas9 unbiased screening in cancer research is to identify genotype-specific vulnerabilities, and AML was the first disease to be systematically analyzed with this technology.(236) Using this platform, the authors found several well-known potential targets for ”
Prioritization of cancer therapeutic targets using CRISPR–Cas9 screens (2019, positive): “PCR amplification, Illumina sequencing (19-bp single-end sequencing with the custom primer on the HiSeq2000 v4 platform) and sgRNA counting were performed as described previously(Tzelepis et al. 2016).”