Co-existence of IL7R high and SH2B3 low expression distinguishes a novel high-risk acute lymphoblastic leukemia with Ikaros dysfunction

Abstract

Acute lymphoblastic leukemia (ALL) remains the leading cause of cancer-related death in children and young adults. Compared to ALL in children, adult ALL has a much lower cure rate. Therefore, it is important to understand the molecular mechanisms underlying high-risk ALL and to develop therapeutic strategies that specifically target genes or pathways in ALL. Here, we explored the IL7R and SH2B3 expression in adult ALL and found that IL7R is significantly higher and Sh2B3 lower expressed in B-ALL compared to normal bone marrow control, and the IL7RhighSH2B3low is associated with high-risk factors, and with high relapse rate and low disease-free survival rate in the patients. We also found that Ikaros deletion was associated with the IL7RhighSH2B3low expression pattern and Ikaros directly binds the IL7R and SH2B3 promoter, and suppresses IL7R and promotes SH2B3 expression. On the other hand, casein kinase inhibitor, which increases Ikaros function, inhibits IL7R and stimulates SH2B3 expression in an Ikaros dependent manner. Our data indicate that IL7RhighSH2B3low expression distinguishes a novel subset of high-risk B-ALL associated with Ikaros dysfunction, and also suggest the therapeutic potential for treatment that combines casein kinase inhibitor, as an Ikaros activator, with drugs that target the IL7R signaling pathway.

Regulation of cellular proliferation in acute lymphoblastic leukemia by Casein Kinase II (CK2) and Ikaros

“…These data demonstrate that CK2 regulates Ikaros ability to repress and to activate its target genes (IL-7R and SH2B3 respectively). These results demonstrate the interplay between the CK2-Ikaros axis and IL7R signaling pathways and provided a mechanistic rationale for the therapeutic efficacy of CK2 inhibitors for treatment of the IL7R-high/SH2B3-low subtype of high-risk B-ALL (Ge et al, 2016a). …”

“…A subset of adult B-ALL patients with high risk factors and poor prognosis have recently been noted to have high IL-7Rα (IL-7R) expression, low SH2B3 expression and Ikaros dysfunction (Ge et al, 2016a). Cell surface IL-7R is required for lymphoid development, but overexpression of IL-7R is considered pro-oncogenic.…”

“…Previous genome wide mapping of Ikaros binding using ChIP-Seq had shown that IL7R and SH2B3 are Ikaros target genes. Expression of IL-7R and SH2B3 were shown by Ge et al to be regulated by Ikaros via chromatin remodeling (Ge et al, 2016a). Ikaros was shown to suppress the promoter activity of IL-7R, while it activated that of SH2B3.…”

Casein Kinase II (CK2), Glycogen Synthase Kinase-3 (GSK-3) and Ikaros mediated regulation of leukemia

“…Subsequent work confirmed the presence of the CK2-Ikaros signaling axis, and its role in regulating expression of a large number of tumor promoters and suppressors in pediatric and adult leukemia (Ge et al, 2015, 2016a, 2016b, 2016c, 2016d, 2017; Wang et al, 2016). Epigenetic analysis of the promoters of Ikaros target genes showed that CK2 regulates not only Ikaros DNA-binding affinity to promoters of its target genes, but also Ikaros-mediated recruitment of HDAC1, as well as the epigenetic signature at regulatory elements of Ikaros targets (Song et al, 2016).…”

“…Overexpression of CK2α and CK2β in hematological malignancies, has been confirmed in several malignancies including B-precursor lymphoblastic leukemia (B-ALL), chronic lymphocytic leukemia (CLL), acute myeloid leukemia (AML), and mature B-cell neoplasms (Ge et al, 2016b; Martins et al, 2010; Pizzi et al, 2015; Quotti Tubi et al, 2013; Scaglioni et al, 2008). In all of the preceding tumors mentioned, further analysis showed a strong correlation between increased level of CK2α and poor clinical outcome.…”