High-risk subtypes of ALL are sensitive to RBM39 degradation. (A) Pearson correlation analysis between RBM39 mRNA and DCAF15 mRNA across the indicated subtypes of B-ALL. Patients with B-ALL mRNA expression data were obtained from the Pediatric Cancer Genome Project data portal (PeCan, St Jude, Memphis). (B) Indisulam area under the curve (AUC) of B-ALL, T-ALL and AML in comparison with nonleukemia cell lines. Data were obtained from the CTD² network⁵³ (left). The indisulam AUC for the indicated B-ALL cell lines (right). (C) IC₅₀ of E7820 (n = 3; the mean value ± standard deviation [SD] is shown) across different B-ALL cell lines as indicated. MEF2D fusion subtypes include Kasumi-7 and -9. (D) The IC₅₀ of E7820 (n = 3; the mean value ± SD is shown) across different B-ALL PDX samples as indicated. (E) Western blot analysis of RBM39 in Kasumi-7 and SUPB15 treated with increasing concentration of E7820 for 4 h. One representative blot is shown on left and quantification of 3 biological replicates is shown on right. (F) Bar graph showing different types of splicing events for patients cells with MEF2D-BCL9 ALL treated with DMSO or E7820 (1 μM) and patient cells with MEF2D-HNRNPUL1 ALL treated with DMSO or E7820 (1 μM). (G-I) MEF2D-HNRNPUL1 ALL PDX cells were transplanted into NSG mice and randomized to E7820 (50 mg/kg) or vehicle, which were orally administrated to mice beginning on day 14 for 6 weeks. The disease burden was monitored by human CD19⁺ cells in peripheral blood (G). ∗P < .05. (H) Spleen weight of mice when the humane end points were reached or on day 75 (end of the study, left; ∗P < .05). Representative images of spleens (right). (I) Survival analysis of the mice administrated with E7820 (50 mg/kg) or vehicle. ∗P < .05.