Co-existence of IL7R high and SH2B3 low expression distinguishes a novel high-risk acute lymphoblastic leukemia with Ikaros dysfunction
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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
Zheng Ge, email: Janege879@hotmail.com
Sinisa Dovat, email: email@example.com
Chunhua Song, email: firstname.lastname@example.org
Keywords: IL7R, SH2B3, Ikaros, gene expression, acute lymphoblastic leukemia
Received: May 18, 2016 Accepted: June 03, 2016 Published: June 14, 2016
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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