Abstract 5540: Transcriptional control of signaling pathways in T-cell lymphoblastic leukemia by Ikaros tumor suppressor

Abstract Cellular proliferation in T-cell acute lymphoblastic leukemia is regulated by multiple signaling pathways. The Phosphoinositide 3-kinase (PI3K)/AKT pathway is frequently dysregulated in T-ALL. Targeting the PI3K pathway has shown promise as a novel therapeutic approach for T-ALL. However, regulation of the PI3K pathway is still not well understood. Here, we report that PI3K activity in T-ALL can be controlled by transcriptional regulation of key members of this pathway, PIK3CD and PIKFYVE. DNA binding analysis of primary T-ALL using qChIP revealed that the tumor suppressor protein, Ikaros, binds the promoter regions of PIK3CD and PIKFYVE. Since Ikaros acts as a regulator of transcription, we tested whether Ikaros binding to PIK3CD and PIKFYVE affects their expression. Overexpression of Ikaros results in reduced transcription of PIK3CD and PIKFYVE in T-ALL. Targeting Ikaros with a specific shRNA, resulted in increased transcription of PIK3CD and PIKFYVE in T-ALL. Together, these results demonstrate that Ikaros functions as a transcriptional repressor of both PIK3CD and PIKFYVE, and suggest that Ikaros can regulate the PI3K pathway in T-ALL. It has been previously shown that Ikaros function in B-cell acute lymphoblastic leukemia is regulated by oncogenic Casein Kinase II (CK2). We tested whether Ikaros ability to repress transcription of PIK3CD and PIKFYVE is regulated by CK2. Inhibition of CK2 by a specific pharmacological inhibitor, CX-4945, resulted in increased Ikaros binding to the promoters of PIK3CD and PIKFYVE, as well as in transcriptional repression of both of these genes. These results suggest that Ikaros function as a repressor of PIK3CD and PIKFYVE transcription is impaired by CK2 in T-ALL. CK2 inhibition restores Ikaros-mediated transcriptional repression of PIK3CD and PIKFYVE, which results in downregulation of the PI3K pathway. In conclusion, the presented data demonstrate that the PI3K signaling pathway is regulated by transcriptional repression of PIK3CD and PIKFYVE by Ikaros in T-ALL. Results reveal interplay between two signaling pathways in T-ALL, CK2 and PI3K, where CK2 positively regulates the PI3K pathway by inhibiting Ikaros function. These data reveal novel mechanisms that regulate cellular proliferation in T-ALL. Citation Format: Tommy Hu, Mario Soliman, Malika Kapadia, Elanora Dovat, Jonathan Payne, Chunhua Song, Sinisa Dovat. Transcriptional control of signaling pathways in T-cell lymphoblastic leukemia by Ikaros tumor suppressor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5540. doi:10.1158/1538-7445.AM2017-5540