Targeting the poison exon of RBM39 with CMGC kinase inhibitors in ALL. (A) Relapsed MEF2D-BCL9 PDX cells were treated with EHT1610 (5 μM) for 16 hours, followed by additional treatment with dinaciclib (5 nM) for 4 hours. PCR reactions were performed for detection of the RBM39 splicing event. (B) Representative western blot analysis of 3 biologic replicates for RBM39 in NALM6 cells treated with dinaciclib, EHT1610, or the combination for 8 hours. (C) ZIP synergy score for EHT1610 and dinaciclib for 3 days in B-ALL cell lines, B-ALL PDX samples, and T-ALL PDX samples. (D) Cell viability assay for control or RBM39 O/E NALM6 cells treated with dinaciclib and EHT1610 for 72 hours (n = 2; ∗P < .05). (E-J) Schematic showing details of dinaciclib and EHT1610 treatment in relapsed MEF2D-BCL9 ALL (E) or Ph-like (H) ALL PDX models. Disease burden was monitored by assessing the human CD19⁺ cells in the peripheral blood (F, I). Survival analysis of relapsed MEF2D-BCL9 ALL (G) or Ph-like (J) ALL PDX. ∗P < .05. O/E, overexpression; ZIP, Zero interaction potency.