Survival for pediatric pre-B cell acute lymphoblastic leukemia (B-ALL) has improved substantially, yet high-risk (HR) subgroups continue to experience significant morbidity and mortality. One molecular feature common in HR ALL is deletion of IKZF1, which reduces the tumor-suppressive activity of the transcription factor IKAROS. Casein kinase 2 (CK2), frequently upregulated in ALL, phosphorylates IKAROS and diminishes its DNA-binding capacity, impairing transcriptional regulation. Prior studies show that pharmacologic CK2 inhibition with CX-4945 can restore IKAROS function. Among IKAROS-regulated targets is the receptor tyrosine kinase c-KIT, which is often overexpressed in cancer. These observations suggest that restoring IKAROS-mediated repression of c-KIT may enhance the activity of c-KIT-targeted therapies such as imatinib. This study evaluated whether CX-4945 synergizes with imatinib in B-ALL cells. Nalm6 cells were treated with imatinib for 72 hours to establish the half-maximal inhibitory concentration (IC50), which was then used to guide concentration ranges for combination testing with CX-4945 in a 72-hour cytotoxicity synergy analysis. Cell viability was assessed using a WST-1 assay, and synergy was defined as a combination index <0.85 using Calcusyn. Experiments were repeated with multiple drug concentrations to refine the synergy window. The IC50 of imatinib as a single agent was 25 μM, while CX-4945 showed an IC50 of 4 μM. When CX-4945 was fixed at 4 μM and imatinib was applied across varying doses, multiple combinations demonstrated synergistic cytotoxicity. These results indicate that CK2 inhibition with CX-4945 enhances the therapeutic efficacy of the c-KIT inhibitor imatinib in B-ALL cells, supporting a cooperative mechanism involving restoration of IKAROS function. Given that imatinib is clinically used for Philadelphia chromosome-positive (Ph+) ALL, future work will assess CX-4945/imatinib synergy in Ph+ B-ALL, where an even more potent effect is anticipated. This combination approach may offer a promising therapeutic avenue for HR ALL subtypes characterized by IKZF1 alteration and chemotherapy resistance.