Enhancing tyrosine kinase inhibitor sensitivity by restoring IKAROS activity on GLUT1 expression and glycolysis in Philadelphia chromosome-positive acute lymphoblastic leukemia.

Many patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) are still less sensitive to tyrosine kinase inhibitors (TKIs). Ph+ ALL shows a high incidence of IKZF1 deletions. Casein kinase II (CK2)-mediated hyperphosphorylation of IKZF1, encoding protein IKAROS, contributes to its dysfunction, and CK2 inhibitor, CX-4945, restores IKAROS function in high-risk ALL. Here, we found that Ph+ ALL cells with IKZF1 deletion are inherently resistant to TKIs. The combination of TKIs (imatinib or ponatinib) with CX-4945 significantly extended the survival and reduced the tumor burden in the IKZF1 deletion (Ik6+) Ph+ ALL patient-derived xenograft (PDX) mouse model; particularly, the patient died of relapse shortly after treatment with the third-generation TKI and the CD19/CD3 bispecific antibody blinatumomab. GLUT1 is highly expressed in the Ph+ ALL and associated with synergy of TKIs with CX-4945; Seahorse assay showed enhanced glycolysis in the patient sample with Ik6+ Ph+ ALL; GLUT1 knockdown suppresses glycolysis and induces apoptosis in the cells. The combination of TKIs with CX-4945 demonstrates the synergistic efficacy through restoring IKAROS transcriptional repression of GLUT1 and further suppressing glycolysis in Ph+ ALL. Our results identify new mechanisms underlying TKI sensitivity and novel approaches to overcome TKI resistance through transcriptional repression of the key genes in glycolysis in Ph+ ALL.