Abstract 286: Synergistic efficacy of CK2 inhibitor with common chemotherapy drugs by restoring Ikaros function in high-risk ALL
Authors: song chunhua , Ge Zheng , Gowda Chandrika , Ding Yali , Payne Jonathon , Tan Bihua , Cury Nathalia M. , Dovat Elanora , Zhao Zhijun , Lyu Xiaoguang , McGrath Mary , Desai Dhimant , lyer Soumya , DhanyamRaju Pavan K. , Payne Kimberly J. , Dovat Sinisa 
Published: August 2019

Objective: IKZF1 gene-coding protein, Ikaros functions as a leukemia suppressor. Casein Kinase II activity is overexpressed in acute lymphoblastic leukemia (ALL) and CK2-mediated-dysfunction of Ikaros is one of the key reason for high-risk ALL and CK2 inhibitor -CX4945 treatment shows high therapeutic efficacy on high-risk ALL. The anti-apoptotic factors are highly expressed in leukemia and the commonly-used 1st-line chemotherapy drugs exerts the anti-tumor effect by suppression of anti-apoptosis signaling. Ikaros binding peaks was identified in the promoter of anti-apoptotic genes by ChIP-seq, suggesting Ikaros regulation on their expression. These observations also suggest the synergistic effect of restoring Ikaros function with common chemotherapy durgs in ALL.

Methods: The ChIP-seq and qChIP assays were performed to determine the enrichment of Ikaros and H3K4me3 in promotor of the genes. Lentiviral Ikaros or IKZF1 shRNA were used for functional analysis. WST-1 cell proliferation assay, Annexin-V staining plus flow cytometry and Patients-derived xenograft mouse (PDX) model were used for observing the anti-tumor effect in vitro and in vivo, respectively.

Results: ChIP-seq and qChIP assays identified Ikaros binding peaks in the promoter of anti-apoptotic genes in cell-lines and patients’ samples. Ikaros overexpression suppresses but IKZF1 knockdown promotes the gene expression. CX-4945 suppresses the expression of the genes by decreasing the H3k27me3 enrichment in an Ikaros and HDAC1-dependent manner in B-ALL cells. The anti-apoptotic gene is significantly up-regulated in ALL patients. CX-4945+chemoterhapy drugs significantly induces the cell proliferation arrest and apoptosis compared to single drugs in vitro and also show the synergistic effect analyzed by CalcuSyn software. CX-4945+chemotherapy drugs significantly reduced the total leukemia cells and % leukemic cells in the three high-risk B-ALL Patient Derived Xenograft (PDX) mice model compared to that of single drugs, which indicated that their synergistic therapeutic efficacy on leukemia development.

Conclusion: Ikaros suppressed anti-apoptotic gene expression through histone modification in ALL. CK2 inhibitor, CX-4945 by restoring Ikaros function have synergistic efficacy with common chemotherapy drugs on high-risk B-ALL.

Citation Format: chunhua song, Zheng Ge, Chandrika Gowda, Yali Ding, Jonathon Payne, Bihua Tan, Nathalia M. Cury, Elanora Dovat, Zhijun Zhao, Xiaoguang Lyu, Mary McGrath, Dhimant Desai, Soumya lyer, Pavan K. DhanyamRaju, Kimberly J. Payne, Sinisa Dovat. Synergistic efficacy of CK2 inhibitor with common chemotherapy drugs by restoring Ikaros function in high-risk ALL [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 286.