Oncotarget

Research Papers:

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

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

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Oncotarget. 2016; 7:46014-46027. https://doi.org/10.18632/oncotarget.10014

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Abstract

Zheng Ge1,2,3, Yan Gu2, Lichan Xiao2, Qi Han2, Jianyong Li2, Baoan Chen1, James Yu4, Yuka Imamura Kawasawa5, Kimberly J. Payne6, Sinisa Dovat3, Chunhua Song3

1Department of Hematology, Zhongda Hospital, Southeast University Medical School, Nanjing 210009, China

2Department of Hematology, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing 210029, China

3Department of Pediatrics, Pennsylvania State University Medical College, Hershey, PA 17033, USA

4Department of Biological Chemistry & Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA

5Penn State Hershey Genome Sciences Facility, Penn State College of Medicine, Hershey, PA 17033, USA

6Department of Pathology and Human Anatomy, Loma Linda University, Loma Linda, CA 92350, USA

Correspondence to:

Zheng Ge, email: Janege879@hotmail.com

Sinisa Dovat, email: sdovat@hmc.psu.edu

Chunhua Song, email: csong@hmc.psu.edu

Keywords: IL7R, SH2B3, Ikaros, gene expression, acute lymphoblastic leukemia

Received: May 18, 2016    Accepted: June 03, 2016    Published: June 14, 2016

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.


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