Abstract 4463: Epigenetic regulation of gene expression in high-risk B-cell acute lymphoblastic leukemia by Casein Kinase II
Authors: Morgann Loaec, Jonathon Payne, Elanora Dovat, Chunhua Song, Kimberly J. Payne, Sinisa Dovat
Journal: Cancer Research (2016)

Abstract Acute lymphoblastic leukemia (ALL) is the most common malignancy in childhood. Although advances in the treatment of ALL have resulted in a high cure rate for this disease, high-risk ALL is characterized by both resistance to conventional chemotherapy and a poor prognosis. The pathogenesis of high-risk ALL is still not understood. Casein Kinase II (CK2) is an oncogenic kinase that is overexpressed in both B-cell ALL (B-ALL) and T-cell ALL (T-ALL) and is associated with poor outcome. Inhibition of CK2 results in a strong therapeutic effect in a preclinical model of leukemia. However, the mechanism by which CK2 promotes oncogenesis in leukemia is unknown. Here, we studied how CK2 regulates expression of histone demethylase KDM5B in ALL. The KDM5B gene encodes a histone demethylase that regulates levels of histone modification H3K4me3 in leukemia. Molecular inhibition of CK2 using shRNA that targets the CK2 catalytic subunit resulted in transcriptional repression of KDM5B in ALL as evidenced by qRT-PCR. A similar effect was observed when leukemia cells were treated with the CK2 inhibitor CX-4945. Inhibition of CK2 resulted in reduced expression of KDM5B with an increase in the global cellular level of H3K4me3 as evidenced by Western blot. The use of quantitative chromatin immunoprecipitation (qChIP) showed that CK2 inhibition enhances DNA binding of the Ikaros tumor suppressor to the promoter of the KDM5B gene. Ikaros is a DNA-binding protein that regulates transcription of its target genes via chromatin remodeling. Loss of Ikaros function results in high-risk ALL. Serial qChIP analysis demonstrated that the increased Ikaros binding to the KDM5B promoter following CK2 inhibition is associated with an alteration of the epigenetic signature at the DNA region that surrounds the Ikaros binding site. Specifically, enhanced Ikaros binding results in increased occupancy of the H3K27me3 histone modification, along with a reduced occupancy of the H3K9ac histone modification at the KDM5B promoter. These results are consistent with the formation of heterochromatin and transcriptional repression. We tested the effect of CK2 inhibitors on Ikaros-mediated repression of KDM5B in primary, high-risk B-ALL cells that have a deletion of one Ikaros allele. Results showed that CK2 inhibition in high-risk B-ALL restores Ikaros binding to KDM5B promoter and represses KDM5B transcription. These data suggest that the inhibition of CK2 controls expression of KDM5B and the global H3K4me3 level in ALL by regulating the function of Ikaros as a transcriptional repressor of KDM5B. This presented data demonstrates the role of the CK2-Ikaros signaling axis in the regulation of both gene expression and the global epigenetic signature in ALL, and provide a mechanistic insight into the role of CK2 in the pathogenesis of ALL. Citation Format: Morgann Loaec, Jonathon Payne, Elanora Dovat, Chunhua Song, Kimberly J. Payne, Sinisa Dovat. Epigenetic regulation of gene expression in high-risk B-cell acute lymphoblastic leukemia by Casein Kinase II. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4463.