Abstract 409: Regulation of chromatin remodeling in leukemia by Ikzf1 and Casein Kinase II

Abstract

Abstract Ikzf1 (Ikaros) encodes a zinc finger protein that binds DNA and regulates gene expression via chromatin remodeling. The loss of Ikaros activity due to genetic or functional inactivation results in leukemia with a poor prognosis. The goal of our project is to determine the mechanism by which Ikaros regulates chromatin remodeling in human leukemia. Previous studies showed that Ikaros function in leukemia is controlled through its direct phosphorylation by Casein Kinase II (CK2). Treatment of leukemia cells with CK2 inhibitors results in enhanced Ikaros activity, which leads to cessation of cell growth. We have studied the mechanism by which inhibition of CK2 regulates Ikaros-induced epigenetic changes in leukemia. The human Nalm6 pre-B cell leukemia was treated with CK2 inhibitor, and the epigenetic signature of the histone modifications H3K9ac and H3K9me3 were determined using chromatin immunoprecipitation coupled with next generation sequencing (ChIP-SEQ). H3K9ac histone modification is associated with positive regulation of gene expression, while H3K9me3 is associated with the formation of heterochromatin and repression. The enrichment of particular histone modifications was confirmed by quantitative chromatin immunoprecipitation (qChIP). The results demonstrated that the inhibition of CK2 activity in leukemia results in a marked alteration in the epigenetic signature of both H3K9ac and H3K9me3 compared to untreated cells. This is associated with altered Ikaros binding to its target genes following CK2 inhibition. Current bioinformatics analysis is directed toward establishing a link between epigenetic modifications and Ikaros binding in leukemia. These results suggest that CK2 and Ikaros regulate gene transcription via epigenetic modifications and chromatin remodeling in leukemia. Citation Format: Jonathon L. Payne, Carlos M. Casiano, Kimberly J. Payne, Justin Sloane, Elanora Dovat, Chunhua Song, Sinisa Dovat. Regulation of chromatin remodeling in leukemia by Ikzf1 and Casein Kinase II. [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 409. doi:10.1158/1538-7445.AM2014-409