Targeting WDR5/ATAD2 signaling by the CK2/Ikaros axis demonstrates therapeutic efficacy in T-ALL

• Identify a novel oncogenic WDR5/ATAD2 signaling by affecting cell cycle progress in T-ALL.

• Targeting WDR5/ATAD2 signaling through the CK2/IKAROS axis demonstrates the synergistic anti-leukemic efficacy in T-ALL.

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy with a poor prognosis and limited options for targeted therapies. Identifying new molecular targets to develop novel therapeutic strategies is the pressing immediate issue in T-ALL. Here, we observed high expression of WD Repeat-Containing Protein 5 (WDR5) in T-ALL; with in vitro and in vivo models we demonstrated the oncogenic role of WDR5 in T-ALL by activating cell cycle signaling through its new downstream effector, ATPase family AAA domain-containing 2 (ATAD2). Moreover, IKAROS' function is often impaired by genetic alteration as well as casein kinase II (CK2) which is overexpressed in T-ALL. We found IKAROS directly regulates WDR5 transcription; CK2 inhibitor, CX-4945 strongly suppresses WDR5 expression by restoring IKAROS function. Lastly, combining CX-4945 with WDR5 inhibitor demonstrates synergistic efficacy in the patient-derived xenograft mouse models. In conclusion, our results demonstrated that WDR5/ATAD2 is a new oncogenic signaling pathway in T-ALL, and simultaneous targeting of WRD5 and CK2/IKAROS has synergistic anti-leukemic efficacy and represents a promising potential strategy for T-ALL therapy.