Ikaros and CK2 regulate expression of Bcl-xL and chemosensitivity in high-risk B-cell acute lymphoblastic leukemia

High-risk B-cell acute lymphoblastic leukemia (B-ALL) is an aggressive disease, often characterized by resistance to chemotherapy. A frequent feature of high-risk B-ALL is loss of function of the Ikaros tumor suppressor. In leukemia, Ikaros’ function is impaired by oncogenic Casein Kinase II (CK2), which is overexpressed in B-ALL. Phosphorylation by CK2 reduces Ikaros binding to the promoter of its target gene, particularly Bcl-xL. This results in a loss of Ikaros-mediated repression of Bcl-xL and in increased expression of Bcl-xL. Increased expression of Bcl-xL and/or CK2, as well as reduced Ikaros expression, are associated with resistance to doxorubicin treatment. Molecular and pharmacological inhibition of CK2 with a specific inhibitor CX-4945, enhances Ikaros-mediated repression of Bcl-xL and increases sensitivity to doxorubicin. Combination treatment with CX-4945 and doxorubicin show synergistic therapeutic effects in vitro and in preclinical models of high-risk B-ALL. Results reveal a novel signaling network that regulates chemoresistance in leukemia and lays the groundwork for clinical testing of CK2 inhibitors in combination with doxorubicin for the treatment of hematopoietic malignancies. Examine the genome-wide binding of Ikaros in JM-1, REH and 697 B-ALL leukemia cells and also the effect of CK2 inhibitor-CX-4945 on the Ikaros binding profiling in JM-1 cells.