CK2 inhibition has an antileukemia effect on primary xenografts of high-risk B-ALL. NRG mice were injected with primary B-ALL cells with deletion of (A) 1 IKZF1 allele or (B-C) other poor prognostic features (supplemental Table 1). (A-C) Following established engraftment (determined as described in Patients, materials, and methods), mice were treated with the CK2 inhibitor, CX-4945, or with vehicle control. Mice were killed and evaluated for the presence of leukemia in BM and spleen at day 22 (patient 3), day 17 (patient 4), or day 26 (patient 5) following the initiation of treatment. Percentages and numbers of leukemia cells in BM or spleen of xenograft mice are graphed. The effect of drug treatment was assessed by Student t test. (D-F) Patient-derived xenografts established with B-ALL from patient 3 (D), patient 4 (E), and patient 5 (F) were treated for 22 days with CK2 inhibitors, CX-4945, or vehicle control and followed for survival. Survival curves were generated using the Kaplan-Meier method, and differences in survival were analyzed by χ2 test. (G-H) Model for the restoration of Ikaros antileukemia activity following CK2 inhibition. (G) Loss of Ikaros tumor suppressor function can occur by genetic inactivation (deletion or inactivating mutation of IKZF1) and/or by functional inactivation due to increased CK2 activity. (H) Targeted inhibition of CK2 kinase restores Ikaros function as repressor of cell cycle progression and the PI3K pathway, which results in an antileukemia effect.
