Clinical significance of high c-MYC and low MYCBP2 expression and their association with Ikaros dysfunction in adult acute lymphoblastic leukemia
2015
// Zheng Ge 1, 2 , Xing Guo 1 , Jianyong Li 1 , Melanie Hartman 2 , Yuka Imamura Kawasawa 3 , Sinisa Dovat 2 , Chunhua Song 2 1 The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Department of Hematology, Nanjing 210029, China 2 Pennsylvania State University College of Medicine, Department of Pediatrics, Hershey, PA 17033, USA 3 Institute for Personalized Medicine, Departments of Biochemistry and Molecular Biology and Pharmacology, Penn State College of Medicine, Hershey, PA 17033, USA Correspondence to: Zheng Ge, e-mail: Janege879@hotmail.com Sinisa Dovat, e-mail: sdovat@hmc.psu.edu Chunhua Song e-mail: csong@hmc.psu.edu Keywords: c-MYC, MYCBP2, Ikaros, adult leukemia, ALL Received: July 14, 2015 Accepted: October 05, 2015 Published: October 17, 2015 ABSTRACT Increased expression of c-MYC is observed in both Acute Myeloid Leukemia (AML) and T-cell Acute Lymphoblastic Leukemia (T-ALL). MYC binding protein 2 (MYCBP2) is a probable E3 ubiquitin ligase and its function in leukemia is unknown. IKZF1 deletion is associated with the development and poor outcome of ALL. Here, we observed significant high c-MYC expression and low MYCBP2 expression in adult ALL patients. Patients with high c-MYC expression and/or low MYCBP2 expression had higher WBC counts and a higher percentage of CD34+ or CD33+ cells, as well as splenomegaly, liver infiltration, higher BM blasts, and lower CR rate. Ikaros bound to the regulatory regions of c-MYC and MYCBP2 , suppressed c-MYC and increased MYCBP2 expression in ALL cells. Expression of c-MYC mRNA was significantly higher in patients with IKZF1 deletion; conversely MYCBP2 mRNA expression was significantly lower in those patients. A CK2 inhibitor, which acts as an Ikaros activator, also suppressed c-MYC and increased MYCBP2 expression in an Ikaros ( IKZF1 ) dependent manner in the ALL cells. In summary, our data indicated the correlation of high c-MYC expression, low MYCBP2 expression and high c-MYC plus low MYCBP2 expression with high-risk factors and proliferation markers in adult ALL patients. Our data also revealed an oncogenic role for an Ikaros / MYCBP2 / c-MYC axis in adult ALL, providing a mechanism of target therapies that activate Ikaros in adult ALL.
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