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

Zheng Ge,Sinisa Dovat,Yan Gu,Jianyong Li,Lichan Xiao,Yuka Imamura Kawasawa,Baoan Chen,Chunhua Song,James Yu,Qi Han,Kimberly J Payne

doi:10.18632/oncotarget.10014

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.

Highlights

Acute lymphoblastic leukemia (ALL), the leading cause of cancer-related death in children and young adults, is less common in adults [1,2,3,4] and treatment outcomes are significantly inferior to those in children [1,2,3, 5, 6]
We found that IL7R high expression negatively correlated with SH2B adaptor protein 3 (SH2B3) expression
The binding of Ikaros at the promoter regions of IL7R and SH2B3 was further confirmed by Quantitative chromatin immunoprecipitation (qChIP) and we found that Ikaros significantly bound to their promoter regions in Nalm6 and Ramos, malignant B cell lines (Figure 3C and 3D) and in primary cells from B-ALL patients (Figure 3E and 3F) but not in Molt 4 and U937 cells (T cell and myeloid leukemias, respectively)

Summary

Introduction

Acute lymphoblastic leukemia (ALL), the leading cause of cancer-related death in children and young adults (aged 21–39), is less common in adults [1,2,3,4] and treatment outcomes are significantly inferior to those in children [1,2,3, 5, 6]. One third of patients with standard-risk ALL and two thirds of high-risk patients relapse, making the cure rate about 40 percent overall in adults [7,8,9]. The reasons underlying this age-related decline in outcome are not completely understood, but it is observed that a higher incidence of genetic alterations is associated with poor outcome, and genetic alterations such as the BCR–ABL1 fusion, are more common in adults than in children [10, 11].

Methods

Results

Conclusion