Abstract 4371: Anti-leukemia effect of Casein Kinase II (CK2) inhibitors in vivo is mediated by the Ikaros tumor suppressor.

Abstract

Abstract An increase in the expression and activity of pro-oncogenic Casein Kinase II (CK2) is associated with the development of acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) in humans. The mechanism by which CK2 promotes leukemogenesis is unknown. Previously, we demonstrated that CK2 kinase phosphorylates the Ikaros tumor suppressor in vivo and that phosphorylation of Ikaros at specific amino acids interferes with the normal function of the Ikaros protein. We hypothesized that CK2 exerts its pro-oncogenic effect by reducing the tumor suppressor activity of Ikaros and that inhibition of CK2 could enhance Ikaros tumor suppressor activity in leukemia. Here we show that Ikaros binds to the promoter regions and represses transcription of several genes that promote cell cycle progression in leukemia. Inhibition of CK2 results in: 1) enhanced Ikaros DNA-binding affinity to its target genes as indicated by quantitative chromatin immunoprecipitation (qChIP) assay); 2) increased Ikaros-mediated transcriptional repression of Ikaros target genes as demonstrated by luciferase reporter assay; 3) impaired proliferation of leukemia cells and 4) increased sensitivity of leukemia cells to Doxorubicin. The use of specific CK2 inhibitors in vivo in a human-mouse leukemia xenograft model produced a strong anti-leukemia effect. Functional analysis of leukemia cells from xenografts demonstrated that CK2 inhibition results in strong binding of Ikaros at the promoters of its target genes and reduced transcription of these genes as indicated by quantitative real-time PCR (qRT-PCR). Our results provide evidence that CK2 inhibitors have a potent anti-leukemia effect in vitro and in vivo, and suggest the mechanism through which CK2 inhibitors exert their therapeutic effect. The presented data demonstrate that one of the mechanisms of action for CK2 inhibitors involves increasing Ikaros activity as a transcriptional repressor in leukemia cells, resulting in enhanced tumor suppressor activity. These results provide a rationale for the use of CK2 inhibitors as a novel therapeutic modality for leukemia. Supported by National Institutes of Health R01 HL095120, a St. Baldrick's Foundation Career Development grant, and the Four Diamonds Fund Endowment (to S.D.). Citation Format: Sinisa Dovat, Chunhua Song, Kimberly J. Payne. Anti-leukemia effect of Casein Kinase II (CK2) inhibitors in vivo is mediated by the Ikaros tumor suppressor. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4371. doi:10.1158/1538-7445.AM2013-4371