Genome-Wide Crispr/Cas9 Screen Reveals That The Dcps Scavenger Decapping Enzyme Is Essential For Aml Cell Survival

Genome-wide knockout screening employing CRISPR-Cas9 genome-editing is a powerful tool for functional genomics. However, identifying actionable targets for cancer therapy has been challenging due, in part, to the complex genetic background of cell lines used for screening. To overcome this obstacle, we generated two acute myeloid leukemia (AML) lines from mouse leukemia models based on activity of the leukemia oncogenes CALM/AF10 or MLL/AF9. Both lines exhibited a normal karyotype and intact Tp53 activity. Using these lines, we performed genome-wide CRISPR-Cas9 screening, followed by a second screen in vivo . We then selected genes meeting the following criteria: 1) they encoded a protein with an available inhibitor or 2) their germline mutation loss-of-function phenotype was relatively moderate based on the literature or the human exome-sequencing database. We excluded genes with a well-defined function in leukemogenesis as well as those encoding components of basal cellular machineries.