CRISPR-Cas9 inactivation of a subset of genes identified in the genome-scale resistance screen impairs lenalidomide-induced degradation of an IKZF3 degron reporter. (A) Schematic of the IKZF3 degron (aa 130-189) reporter vector. (B) Schematic of flow cytometry–based sorting of cells in which degradation of the IKZF3 degron reporter has been impaired by CRISPR-Cas9 inactivation of target genes. (C) Genes from the reporter screen ranked according to the average fold-change in the log2-transformed gRNA sequencing read counts (lenalidomide-treated eGFP⁺/DMSO). Fold-change values are normalized to the average fold-change of 12 control gRNAs. Each point represents an individual gRNA, and each point is the average of 3 infection replicates. *FDR < 0.05, 1-sided Wilcoxon rank-sum test.