Combinatorial inhibition of menin-MLL and IGF2BP3 increases survival in vivo and is accompanied by concordant changes in gene expression. (A-B) Increased overall survival and leukemia survival with IGF2BP3 knockdown and MI-503 treatment in NT groups (n = 8 mice per group; Kaplan-Meier with log-rank test, ∗P < .05; ∗∗P < .01; ∗∗∗P < .001). Comparisons made vs NT DMSO. Follow-up to 15 weeks with terminal sac of remaining mice. (C) Photomicrographs of Wright-stained BM smears from mice as above; original magnification, ×1000; scale bar, 10 μm. (D-F) Expression of genes of interest in the BM of mice that received transplantation with MI-503–treated MLL-Af4 Lin^– NT or I3KO cells was measured by qRT-PCR. MLL-Af4 Lin^– cells depleted (I3KO) or nondepleted (NT) for IGF2BP3 were treated with MI-503 0.5 mM (MI-503) or carrier control (DMSO) for 5 days in vitro before transplantation. Mice were euthanized at 8.5 weeks at first signs of the first mouse developing terminal leukemia. Gene expression data shown from selected mice in each group. Shown as fold change from NT DMSO (mean ± SD; n = 2; 1-way ANOVA with Bonferroni multiple comparisons test, ∗P < .05; ∗∗ P < .01; ∗∗∗P < .001; ∗∗∗∗ P < .0001).