Abstract C44: Epigenetic regulation of CRLF2 oncogene expression by Casein Kinase II (CK2) signaling in B-cell acute lymphoblastic leukemia that occurs at high frequency in Hispanic children

Abstract

Abstract B-cell acute lymphoblastic leukemia (B-ALL) occurs more frequently in Hispanic children as compared to non-Hispanic whites. The specific subtype of B-ALL that is caused by overexpression of CRLF2 (CRLF2 B-ALL), occurs 5 times more frequently in Hispanic children as compared to the others. Since this type of B-ALL is associated with poor prognosis, the death rate of B-ALL is 39% higher in Hispanic children than in non-Hispanic whites. Thus, understanding the molecular mechanisms that regulate CRLF2 expression in CRLF2 B-ALL is essential for the development of targeted therapy for this disease. Our previous work determined that transcription of CRLF2 is negatively regulated by a tumor-suppressor protein, Ikaros. Ikaros deregulation is a feature of over 80% of CRLF2 B-ALL. Here we present evidence that Ikaros-mediated repression of CRLF2 transcription in B-ALL in Hispanic children is regulated by Casein Kinase II (CK2). CK2 is an oncogenic kinase that is overexpressed in B-ALL. We have previously shown that CK2 can directly phosphorylate Ikaros and that phosphorylation by CK2 can impair Ikaros function as transcriptional regulator. We tested whether inhibition of CK2 affects the ability of Ikaros to regulate CRLF2 transcription. Molecular inhibition by shRNA that targets the catalytic subunit of CK2, as well as pharmacologic inhibition of CK2 by the specific inhibitor, CX-4945, resulted in reduced expression of CRLF2 as measured by qRT-PCR. This was associated with increased Ikaros binding to the CRLF2 promoter as measured by quantitative chromatin immunoprecipitation (qChIP). To determine whether Ikaros function is essential for CRLF2 repression following CK2 inhibition, we compared expression of CRLF2 in cells that have Ikaros knocked-down by shRNA vs. cells with control shRNA, following treatment with CX-4945. Results showed that Ikaros knockdown abolished the ability of CK2 inhibitors to repress transcription of CRLF2 in B-ALL. These results demonstrate that Ikaros is an essential component of CK2 signaling that regulates CRLF2 expression. Analysis of the epigenetic signature at the CRLF2 promoter performed by serial qChIP assays showed that increased Ikaros binding to the CRLF2 promoter, following CK2 inhibition, is associated with enrichment for the H3K9me3 histone modification, which is a marker of repressive chromatin. In conclusion, we demonstrate that expression of the CRLF2 oncogene in acute leukemia that disproportionally occurs in Hispanic children is epigenetically regulated by the CK2-Ikaros axis. In CRLF2 B-ALL, Ikaros-mediated repression of CRLF2 is impaired due to overexpression of CK2. Treatment of CRLF2 B-ALL with CK2 inhibitors restores Ikaros tumor suppressor function, resulting in CRLF2 repression. Results identified a signaling network that regulates CRLF2 expression and suggest that restoration of Ikaros activity with CK2 inhibitors can be a therapeutic approach for CRLF2 B-ALL to reduce the health disparity for Hispanic children with ALL. Supported by 1R01CA209829. Citation Format: Chunhua Song, Zheng Ge, Kimberly J. Payne, Sinisa Dovat. Epigenetic regulation of CRLF2 oncogene expression by Casein Kinase II (CK2) signaling in B-cell acute lymphoblastic leukemia that occurs at high frequency in Hispanic children [abstract]. In: Proceedings of the Tenth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2017 Sep 25-28; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2018;27(7 Suppl):Abstract nr C44.