Combination benefit between BCL2 and KDM5-family inhibitors in SETD1B deficient lymphoma. (A) RT-qPCR analysis of the relative expression of BIK in OCI-LY19; sgSETD1B vs. OCI-LY19; sgLacZ cells treated with DMSO or 1 μM JIB-04 for 24 h. Results were represented as mean ± SD (n = 3). P values were calculated by two-way ANOVA followed by Tukey’s multiple comparisons test. ****P < 0.0001; n.s.: non-significant. (B) IC₅₀ curves at 72 h of JIB-04 in OCI-LY19 cells carrying sgRNA targeting LacZ (sgLacZ) or SETD1B (sgSETD1b) knockout single-cell clone. Values represent the average of three independent dose-titration curves (n = 3). (C and D) Cell viability values in (C) OCI-LY19;sgSETD1B and (D) OCI-LY19;sgLacZ cell lines in response to Venetoclax and JIB-04 combined treatment for 72 h, as assessed by CellTiter-Glo assay. Values represent the average of three independent dose-titration curves (n = 3). Combination index at IC₅₀ = 0.382 ± 0.014 calculated from the combination index equation algorithms (Chou, 2010) using CompuSyn software. (E and F) (E) Tumor volumes and (F) weight of OCI-LY19; sgSETD1B xenograft model treated with vehicle (p.o. QDx5); JIB-04 (50 mg/kg p.o. QDx5); Venetoclax (100 mg/kg p.o. QDx5); or with JIB-04 50 mg/kg p.o. QDx5 + Venetoclax 100 mg/kg p.o. QDx5. Treatment with JIB-04 started 5 days prior to the treatment with Venetoclax. Data represent the mean percentage ± SEM (n = 8 animal/group). P values were calculated by two-way ANOVA followed by Tukey’s multiple comparisons test. ****P < 0.0001; ***P = 0.0006.