Abstract 2927: Targeted combination treatment for B-cell acute lymphoblastic leukemia

The CCND3 gene encodes Cyclin D3–a protein that is essential for G1/S cell cycle progression and proliferation of malignant cells. Targeting Cyclin D3 is used to treat B-cell acute lymphoblastic leukemia (B-ALL); however, the mechanisms that regulate expression of the CCND3 gene in B-ALL are largely unknown. Here, we present evidence that oncogenic Casein Kinase II (CK2) regulates expression of CCND3 and G1/S cell cycle progression via direct phosphorylation of Ikaros, a transcription regulator and tumor suppressor protein. Global genome-wide DNA-binding analysis using ChIP-seq, show that Ikaros binds the promoter of CCND3 in primary human B-ALL. The role of Ikaros in regulating CCND3 expression in B-ALL was tested using gain-of-function and loss-of-function experiments. Ikaros knock-down with shRNA results in increased transcription of CCND3 in B-ALL. Overexpression of Ikaros in human B-ALL was associated with reduced expression of CCND3. Since Ikaros activity in leukemia is regulated by pro-oncogenic Casein Kinase II (CK2), we tested whether CK2 regulates expression of CCND3 in B-ALL. Increased expression of CK2 in B-ALL results in increased expression of the CCND3 gene. This was associated with a loss of Ikaros binding to the promoter of the CCND3 gene. Inhibition of CK2 with shRNA, and/or a specific CK2 inhibitor, CX-4945, resulted in increased Ikaros binding to the CCND3 promoter and reduced expression of Cyclin D3 in B-ALL. Treatment with CX-4945 showed strong therapeutic activity in preclinical models of B-ALL. A combination treatment with CX-4945 and dexamethasone that targets G1/S cell cycle progression shows a strong synergistic effect on B-ALL cells. In conclusion, presented data show that CK2 and Ikaros regulate G1/S cell cycle progression via transcriptional regulation of the CCND3 gene in B-ALL and that CK2 inhibition represses CCND3 expression by enhancing Ikaros tumor suppressor function. Results demonstrate the synergistic efficacy of a combination treatment with CK2 inhibitor and dexamethasone and provide a rationale for the use of this combination treatment as a novel therapeutic approach for B-cell acute lymphoblastic leukemia.Citation Format: Shriya Kane, Yali Ding, Chandrika Gowda, Jonathon Lee Payne, Soumya Iyer, Pavan K. Dhanyamraju, Chunhua Song, Dhimant Desai, Arati Sharma, Kimberly J. Payne, Sinisa Dovat. Targeted combination treatment for B-cell acute lymphoblastic leukemia [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2927.