Co-existence of IL7R high and SH2B3 low expression distinguishes a novel high-risk acute lymphoblastic leukemia with Ikaros dysfunction.
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.
Department of Hematology, Zhongda Hospital, Southeast University Medical School, Nanjing 210009, China.|Department of Hematology, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing 210029, China.|Department of Pediatrics, Pennsylvania State University Medical College, Hershey, PA 17033, USA.
Zheng
Z
Ge
Department of Hematology, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing 210029, China.
Yan
Y
Gu
Department of Hematology, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing 210029, China.
Lichan
L
Xiao
Department of Hematology, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing 210029, China.
Qi
Q
Han
Department of Hematology, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing 210029, China.
Jianyong
J
Li
Department of Hematology, Zhongda Hospital, Southeast University Medical School, Nanjing 210009, China.
Baoan
B
Chen
Department of Biological Chemistry & Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.
James
J
Yu
Penn State Hershey Genome Sciences Facility, Penn State College of Medicine, Hershey, PA 17033, USA.
Yuka Imamura
YI
Kawasawa
Department of Pathology and Human Anatomy, Loma Linda University, Loma Linda, CA 92350, USA.
Kimberly J
KJ
Payne
Department of Pediatrics, Pennsylvania State University Medical College, Hershey, PA 17033, USA.
Sinisa
S
Dovat
Department of Pediatrics, Pennsylvania State University Medical College, Hershey, PA 17033, USA.
Chunhua
C
Song
D048868:Adaptor Proteins, Signal Transducing; D000328:Adult; D014408:Biomarkers, Tumor / Q000032:analysis; D018572:Disease-Free Survival; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D006801:Humans; D051740:Ikaros Transcription Factor / Q000235:genetics*; D053699:Interleukin-7 Receptor alpha Subunit / Q000096:biosynthesis*; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics* / Q000378:metabolism / Q000401:mortality; D011506:Proteins / Q000378:metabolism*
D048868:Adaptor Proteins, Signal Transducing; D014408:Biomarkers, Tumor; C497239:IKZF1 protein, human; C000620371:IL7R protein, human; D053699:Interleukin-7 Receptor alpha Subunit; D047908:Intracellular Signaling Peptides and Proteins; D011506:Proteins; C490778:SH2B3 protein, human; D051740:Ikaros Transcription Factor
IL7R; Ikaros; SH2B3; acute lymphoblastic leukemia; gene expression