The combination of CX-4945 and WDR5 disruption has a synergistic antileukemic effect in the T-ALL mice model. (A) Schematic representation of the human T-ALL CEM cell-xenograft mouse model (CEM xenograft). CEM (2 × 105 per mouse) were IV injected into NCG mice, and the following 4 groups of mice were established: group 1 (vehicle control); group 2 (CX-4945 daily through gavage at 100 mg/kg for 25 days); group 3 (WDR5 inhibitor OICR-9429 every 2 days through intraperitoneal injection at 60 mg/kg for 25 days); and group 4 (CX-4945 and OICR-9429 combination treatment using the same doses as provided previously). (B) Comparison of Kaplan-Meier survival curves in the combination of CX-4945 and WDR5 inhibitor OICR-9429 compared with either single drug control of CEM-xenograft mouse models. The mice were treated with the indicated drugs for 25 days. (C-D) Spleen images (C) and weights (D) of 4 groups of mice posttreatment. (E) The percentage of human CD45+ and CD7+ cells in the spleen and BM from 4 groups of mice post-treatment. (F-G) Representative immunohistological images (F) and quantitation data (G) of human CD45 in the spleen from 4 groups of mice post-treatment. (H) The protein level of WDR5 and ATAD2 and the internal control of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) in the spleen tissues of the mice after the treatment. (I) mRNA level of WDR5, ATAD2, CCNE2, and CDK2 in the spleen tissues of the mice after the treatment. Scale bar, 50 μm. ∗∗∗P < .001. i.g., intragastic gavage; i.p., intraperitoneal injection; OI, OICR-9429.
