Combinatorial inhibition of menin-MLL and IGF2BP3 decreases leukemic engraftment and burden and increases survival in vivo. (A) Schematic representation of BM transplantation of MI-503–treated MLL-Af4 Lin^– cells, depleted (I3KO) or nondepleted (NT) for IGF2BP3. Cells treated with MI-503 0.5 μM (or DMSO control) for 5 days in vitro were transplanted into CD45.1 recipients after busulfan conditioning. (B) Decreased peripheral blood engraftment of leukemic cells by CD45.2⁺ percentage with MI-503 treatment and I3KO at D42 (mean ± SD; n = 8 mice per group; 1-way ANOVA with Bonferroni multiple comparison’s test, ∗ P < .05). (C) Decreased proportion of mice with leukemia with MI-503 treatment and IGF2BP3 knockdown, (8 mice per group; Fisher exact test; ∗ P < .05; ∗∗ P < .01). Mice were all evaluated at necropsy at 8.5 weeks after the first mouse developed signs of terminal leukemia. (D-I) Decreased leukemic burden seen with IGF2BP3 knockdown and MI-503 treatment in NT groups, based on total counts, CD11b⁺ counts, and CD45.2⁺ percentage by flow cytometry in the spleen (D-F) and BM (G-I) (mean ± SD; n = 7-8 mice per group; 1-way ANOVA with Bonferroni multiple comparison’s test, ∗P < .05; ∗∗P < .01; ∗∗∗P < .001; ∗∗∗∗P < .0001). Mice were all evaluated at necropsy at 8.5 weeks after the first mouse developed signs of terminal leukemia.