Transcriptional Regulation of PIK3CD and PIKFYVE in T-Cell Acute Lymphoblastic Leukemia by IKAROS and Protein Kinase CK2.

Elanora Dovat,Daniel Bogush,Mario Soliman,Yali Ding,Pavan Kumar Dhanyamraju,Mohammad Atiqur Rahman,Tommy Hu,Mary Mcgrath,Shriya Kane,Chunhua Song,Dhimant Desai,Morgann Klink,Chandrika Gowda,Arati Sharma

doi:10.3390/ijms22020819

Abstract

IKAROS, encoded by the IKZF1 gene, is a DNA-binding protein that functions as a tumor suppressor in T cell acute lymphoblastic leukemia (T-ALL). Recent studies have identified IKAROS’s novel function in the epigenetic regulation of gene expression in T-ALL and uncovered many genes that are likely to be directly regulated by IKAROS. Here, we report the transcriptional regulation of two genes, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit delta (PIK3CD) and phosphoinositide kinase, FYVE-type zinc finger containing (PIKFYVE), by IKAROS in T-ALL. PIK3CD encodes the protein p110δ subunit of phosphoinositide 3-kinase (PI3K). The PI3K/AKT pathway is frequently dysregulated in cancers, including T-ALL. IKAROS binds to the promoter regions of PIK3CD and PIKFYVE and reduces their transcription in primary T-ALL. Functional analysis demonstrates that IKAROS functions as a transcriptional repressor of both PIK3CD and PIKFYVE. Protein kinase CK2 (CK2) is a pro-oncogenic kinase that is overexpressed in T-ALL. CK2 phosphorylates IKAROS, impairs IKAROS’s DNA-binding ability, and functions as a repressor of PIK3CD and PIKFYVE. CK2 inhibition results in increased IKAROS binding to the promoters of PIK3CD and PIKFYVE and the transcriptional repression of both these genes. Overall, the presented data demonstrate for the first time that in T-ALL, CK2 hyperactivity contributes to PI3K signaling pathway upregulation, at least in part, through impaired IKAROS transcriptional regulation of PIK3CD and PIKFYVE. Targeting CK2 restores IKAROS’s regulatory effects on the PI3K oncogenic signaling pathway.

Highlights

Introduction censeeMDPI, Basel, Switzerland.IKAROS is a zinc finger protein encoded by the IKZF1 gene
As shown in previous studies [22,32,38], we found increased expression of the CK2α protein in T cell leukemia cells compared to normal peripheral blood mononuclear cells (MNCs) (Figure 1B)
CK2α expression correlated with increased phosphorylated IKAROS in T- cell Acute Lymphoblastic Leukemia (T-acute lymphoblastic leukemia (ALL)) cells (Figure 1C)

Summary

Introduction

IKAROS is a zinc finger protein encoded by the IKZF1 gene. IKAROS binds to DNA and functions as a transcriptional regulator of its target genes via chromatin remodeling [1]. IKAROS-knockout mice develop T cell malignancy with 100% penetrance [2]. Inactivation of IKAROS by a recurrent genetic alteration in the IKZF1 gene is seen in nearly 4–5% of adult and pediatric T- cell Acute Lymphoblastic Leukemia (T-ALL) and is associated with poor outcome [3,4,5,6]. T cell precursor (ETP) leukemia is a distinct subtype of T-ALL, ms in published maps and institutio-

Methods

Results

Conclusion