Abstract 2632: Casein kinase II inhibitors regulate cell cycle progression in leukemia

Abstract

Abstract Casein Kinase II (CK2) is an oncogenic kinase that is overexpressed in leukemia. The molecular mechanism by which CK2 exerts its oncogenic function is largely unknown. We have previously demonstrated that CK2 directly phosphorylates the Ikaros tumor suppressor in vivo at multiple, evolutionarily conserved amino acids. CK2-mediated phosphorylation of Ikaros results in reduced DNA binding affinity, loss of pericentromeric localization and impaired Ikaros transcriptional repression. We hypothesize that the pro-oncogenic activity of CK2 in leukemia involves functional inactivation of Ikaros, and that CK2 inhibition will result in restoration of the tumor suppressor function of Ikaros and an anti-leukemia effect. To test this hypothesis, we have tested the effect of specific CK2 inhibitors on Ikaros function as a transcriptional regulator of genes that promote cell cycle progression. Using quantitative Chromatin Immunoprecipitation (qChIP), we have shown that Ikaros binds to the promoters of two genes that are essential for mitosis, ANAPC1 and ANAPC7, in leukemia cell lines and in primary leukemia cells. Increased expression of Ikaros via retroviral transduction was associated with increased binding of Ikaros to the promoters of ANAPC1 and ANAPC7 and their transcriptional repression. Luciferase reporter assay was used to confirm that Ikaros can directly repress transcription of both ANAPC1 and ANAPC7. These data suggest that Ikaros negatively regulates cell cycle progression during mitosis and that Ikaros function as a repressor of ANAPC1 and ANAPC7 is impaired in leukemia. We tested the ability of CK2 inhibition to restore Ikaros repressor activity in leukemia. We evaluated the pre-B acute lymphoblastic leukemia (B-ALL) cell line, Nalm6 treated with a specific CK2 inhibitor, TBB as well as in a murine preclinical xenograft model of B-ALL. CK2 treatment resulted in increased Ikaros binding to promoters of ANAPC1 and ANAPC7, along with transcriptional repression of both genes. This was associated with prolonged survival of B-ALL xenograft mice that were treated with CK2 inhibitors. These data suggest that CK2 inhibitors can regulate cell cycle progression in leukemia cells by restoring the transcriptional repressor function of Ikaros. Our results demonstrate efficacy of CK2 inhibitors as a novel treatment for leukemia. Citation Format: Chandrika Gowda, Chunhua Song, Mansi Sachdev, Xiaokang Pan, Yali Ding, Kimberley Payne, Sinisa Dovat. Casein kinase II inhibitors regulate cell cycle progression in leukemia. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2632. doi:10.1158/1538-7445.AM2014-2632