Abstract 846: Transcriptional regulation of Aurora-B kinase expression in B-cell acute lymphoblastic leukemia (B-ALL)

Abstract

Abstract The Aurora kinases are serine/threonine kinases that are essential for mitosis. Aurora-B kinase is a component of the chromosomal passenger complex (CPC), chromosome condensation, the spindle-assembly checkpoint, and for cytokinesis. The activity of Aurora-B is essential for cellular division and proliferation. Inhibition of Aurora-B is cytotoxic, and inhibitor of Aurora-B - Barasertib (AZD1152) has been tested in clinical trials against different types of malignancies, including leukemia. However, regulation of Aurora-B expression is still largely unknown. Here, we present evidence that expression of Aurora-B in B-cell acute lymphoblastic leukemia (B-ALL) is regulated at the transcriptional level by Ikaros, a transcription factor and tumor suppressor protein. Analysis of global chromatin immunoprecipitation coupled with next-generation sequencing (ChIP-seq) in several B-ALL primary human B-ALL cells and cell lines, showed a strong enrichment of Ikaros at the promoter of the Aurora-B gene. Ikaros functions as a tumor suppressor protein and deletion of Ikaros is associated with development of high-risk B-ALL. Ikaros binding to Aurora-B promoter was confirmed by quantitative chromatin immunoprecipitation (qChIP) in primary B-ALL cells. The role of Ikaros in regulating Aurora-B transcription in B-ALL was tested using gain-of-function and loss-of-function experiments. Overexpression of Ikaros in human B-ALL was associated with strongly reduced transcription and overall expression of Aurora-B. Ikaros knock-down with shRNA results in increased expression of Aurora-B in B-ALL. Since Ikaros function in B-ALL is negatively regulated by pro-oncogenic Casein Kinase II (CK2), we tested whether CK2 can regulate expression of Aurora-B in B-ALL. Overexpression of CK2 via retroviral transduction resulted in increased expression of the Aurora-B gene. Increased expression of CK2 was associated with a loss of Ikaros binding to the Aurora-B gene promoter. Molecular inhibition of CK2 using shRNA resulted in reduced expression of Aurora-B in human B-ALL. Inhibition of CK2 was associated with increased Ikaros binding at the Aurora-B promoter. Ikaros knock-down abolished downregulation of Aurora-B expression in B-ALL cells following treatment with CK2 inhibitors. These data demonstrate that CK2 and Ikaros are critical regulators of Aurora-B expression in B-ALL. In conclusion, these results indicate that expression of the Aurora-B gene in B-ALL is regulated by the CK2-Ikaros signaling axis and provide a novel insight into mechanisms that regulate mitosis in leukemia. Citation Format: Yali Ding, Chunhua Song, Joseph Schramm, Soumya Maru, Daniel Bogus, Dhimant H. Desai, Arati K. Sharma, Chandrika Gowda, Sinisa Dovat. Transcriptional regulation of Aurora-B kinase expression in B-cell acute lymphoblastic leukemia (B-ALL) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 846.