Synthetic lethal interaction of RBM10 loss with NFκB. (A) CRISPR/Cas9 dropout screen strategy to identify genes required for cell survival in RBM10-null KTC1 cells; illustration by Biorender (top). Volcano plot (bottom) showing relative fold change of depleted genes (light blue) in pLVX versus RBM10-expressing KTC1 cells calculated from an average of four sgRNAs targeting each gene. Gene label, red: Top 10 depleted genes; blue: other relevant hits. (B) KEGG pathway enrichment analysis performed in ShinyGO tool showing activation of NFκB and NFκB-related pathways (red). (C) Western blot of pNFκB (p65) and total NFκB in PE121410 and KTC1 cells at baseline and in the presence of TNFα. (D) Western blot demonstrating dox-induced KD of RELA (NFκB) in KTC1 cells. (E) Effect dox-induced KD of RELA on growth of RBM10-mutant KTC1 cells. Data represent SEM of three replicates at each time point. (F) Dose-response curves of KTC1 cells ± RBM10 treated with various concentrations of TPCA in the presence of TNFα in 1% FBS. (G) Effect of RELA KD on apoptosis in the presence or absence of TNFα (100 ng/ml) and dabrafenib (200 nM) as determined by annexin flow cytometry in KTC1 cells. Data represent mean with SD of three replicates; statistical difference was analyzed by unpaired t test (***P < 0.0001). Source data are available for this figure: SourceData F5.