Oncotarget

Research Papers:

Clinical significance of high c-MYC and low MYCBP2 expression and their association with Ikaros dysfunction in adult acute lymphoblastic leukemia

Zheng Ge _, Xing Guo, Jianyong Li, Melanie Hartman, Yuka Imamura Kawasawa, Sinisa Dovat and Chunhua Song

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Oncotarget. 2015; 6:42300-42311. https://doi.org/10.18632/oncotarget.5982

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Abstract

Zheng Ge1,2, Xing Guo1, Jianyong Li1, Melanie Hartman2, Yuka Imamura Kawasawa3, Sinisa Dovat2, Chunhua Song2

1The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Department of Hematology, Nanjing 210029, China

2Pennsylvania State University College of Medicine, Department of Pediatrics, Hershey, PA 17033, USA

3Institute 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: [email protected]

Sinisa Dovat, e-mail: [email protected]

Chunhua Song e-mail: [email protected]

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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