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

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.

Reversal of IKZF1-induced glucocorticoid resistance by dual targeting of AKT and ERK signaling pathways

“…Similar to what has been observed in primary patient samples, disrupted IKZF1 expression led to increased resistance against prednisolone treatment. Analogous to what has been observed in T-ALL (14), a loss of IKZF1 expression was accompanied by enhanced phosphorylation of AKT, while total AKT protein expression remained unaffected (Figure 1A and Supplemental Figure 2A). To demonstrate that the effect on AKT phosphorylation was a direct consequence of IKZF1 loss, and independent of the leukemic context, we investigated AKT status in LPS-activated B cells from Ikzf1 +/mice (Supplementary Figures 3A, B).…”

“…Recently, IKZF1 was identified as transcriptional repressor of two PI3K pathway related genes (PIK3CD and PIKFYVE) in T-ALL (14), leading to the induction of AKT signaling in response to IKZF1 loss. In T-ALL, AKT1 activity was shown to be a determinant of GC resistance, driving phosphorylation of the GR to prevent its nuclear translocation and, consequently, glucocorticoid-induced gene expression (15).…”

Protein kinase CK2 – diverse roles in cancer cell biology and therapeutic promise

“…Importantly, CK2 inhibition restores Ikaros functionality as evidenced by repression of BCL2L1 (Bcl-XL) levels and induction of cell death in B-cell acute lymphoblastic leukemia (ALL) cells [ 150 , 151 ]. It was further demonstrated in T-cell ALL that elevation of CK2 activity contributes to PI3K signaling pathway upregulation in part through impaired Ikaros function [ 152 ]. The ability of CK2 levels to subvert the functions of this tumor suppressing epigenetic regulator in leukemia cells emphasizes the impact of elevated CK2 levels in the nucleus of malignant cells.…”

The Role of Protein Kinase CK2 in Development and Disease Progression: A Critical Review

“…CK2 also has a critical role in mammalian target of rapamycin (mTOR) signaling. Specifically, the inhibition of CK2 expression is associated with an increased activity of Ikaros, which binds to the mTOR gene to suppress its activity and prevent tumor formation [ 96 , 97 , 98 , 99 , 100 ]. However, the overexpression of CK2 subsequently increases mTOR signaling, leading to poor outcomes such as tumorigenesis and cancer progression [ 101 , 102 , 103 , 104 ].…”

“…CK2 overexpression and/or overactivity results in the abnormal phosphorylation of its targets. One example is tumor suppressor Ikaros, which is a transcriptional repressor of the genes encoding for Bcl-2-like protein 1 ( BCL2L1 , PIK3CD , and PIKFYVE ) [ 98 , 100 ].…”