KDM5 inhibition reduces the proliferation of KMT2D mutant cell lines. (A-B) DLBCL, FL, myeloma, and Burkitt’s lymphoma cell lines were treated with DMSO or increasing concentrations of KDM5-inh1, and viable cells were quantified every day up to 6 days for OCI-LY-18, SU-DHL-6, and HT cells (A) and after 5 days for all cell lines (B), with EC₅₀ values for KMT2D WT and mutant cell lines displayed in a waterfall plot. (C) Dot plot showing the significantly lower EC₅₀ values for KMT2D mutant cell lines. Statistical significance was determined by Mann-Whitney U test: **P < .01. (D) Induction of apoptosis was quantified in OCI-LY-18, SU-DHL-6, and HT cells treated with DMSO or increasing concentrations of KDM5-inh1 for 5 days. (E) Western blots showing loss of KDM5A in 3 homozygous knockout clones (SU6-A3, A30, A50) compared with parental and WT controls (SU6#33, #34), alongside expression of KDM5C, BCL2, and H3K4me3 levels. (F) Parental, control, and KDM5A knockout SU-DHL-6 cells were seeded at 4000 cells per well, and viable cell numbers were quantified after 6 days. Statistical significance was calculated using a 2-way analysis of variance (ANOVA) with a Tukey’s posttest: *P < .05 and ***P < .001 relative to SU6#33, and ^#P < .05 relative to SU6#34. (G-H) Viable cell counts from WSU-DLCL2 cells and 3 KMT2D mutant clones (G) or parental SU-DHL-8 cells and 3 corrected clones (H) treated with DMSO or increasing concentrations of KDM5-inh1 for 5 days. Data are the mean ± standard error of the mean of 3 to 7 independent experiments. Statistical significance was calculated using a 2-way ANOVA with a Dunnett’s posttest: *^/#P < .005; ***P < .001.