Loss of SETD1B impairs response to BCL2 and MCL-1 inhibition. (A and B) Dot plots illustrate the top candidate genes identified through CRISPR screening for (A) Venetoclax and (B) MCL-1 inhibitor (S63845). Genes are ranked by the average Log2FC (FC after treatment vs. before treatment) of all significantly enriched sgRNAs targeting the respective gene. (C) IC₅₀ curves depict the response of OCI-LY19 cells to Venetoclax. The cells carry either Cas9 alone, Cas9 with sgRNA targeting LacZ (sgLacZ), or sgRNAs targeting SETD1B (sgSETD1B, single-cell clones without detectable SETD1B protein) generated from two independent sgRNAs. Values represent the average of three independent dose-titration curves (n = 3). (D) Bar graphs displaying measurements of mitochondrial cytochrome c release, reflecting mitochondrial depolarization, following treatment with DMSO or Venetoclax. Alamethicin treatment triggers the complete release of mitochondrial cytochrome c (100% mitochondrial depolarization) and serves as a positive control. (E) Relative growth curve of xenografted OCI-LY19; sgLacZ treated with vehicle (n = 5) or 100 mg/kg of Venetoclax (n = 5). P value was calculated using Student’s t test (*P < 0.05). (F) Relative growth curve of xenografted OCI-LY19;sgSETD1B (sg1; clone 1) treated with vehicle (n = 5) or Venetoclax (n = 5). P value was calculated using Student’s t test (n.s.: not significant).