Oncotarget

Research Papers:

Ikaros regulation of the BCL6/BACH2 axis and its clinical relevance in acute lymphoblastic leukemia

Zheng Ge _, Xilian Zhou, Yan Gu, Qi Han, Jianyong Li, Baoan Chen, Qinyu Ge, Elanora Dovat, Jonathon L. Payne, Tianyu Sun, Chunhua Song and Sinisa Dovat

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Oncotarget. 2017; 8:8022-8034. https://doi.org/10.18632/oncotarget.14038

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Abstract

Zheng Ge1,2, Xilian Zhou3, Yan Gu3, Qi Han3, Jianyong Li3, Baoan Chen1,2, Qinyu Ge4, Elanora Dovat5, Jonathon L. Payne5,6, Tianyu Sun7, Chunhua Song2,5, Sinisa Dovat2,5

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

2International Cooperative Leukemia Group and International Cooperative Laboratory of Hematology, Zhongda Hospital, Medical School of Southeast University, Nanjing 210009, China

3Department of Hematology, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing 210029, China

4State Key Laboratory of Bioelectronics, School of Biological Science and Medical Engineering, Southeast University, Nanjing 210096, China

5Department of Pediatrics, Pennsylvania State University Medical College, Hershey, PA 17033, USA

6Loma Linda University School of Medicine, Department of Basic Sciences, Loma Linda, CA 92350, USA

7Department of Internal Medicine, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA

Correspondence to:

Zheng Ge, email: [email protected]

Sinisa Dovat, email: [email protected]

Keywords: BCL6, BACH2, IKZF1, acute lymphoblastic leukemia

Received: October 11, 2016     Accepted: November 24, 2016     Published: December 20, 2016

ABSTRACT

B-Cell CLL/Lymphoma 6 (BCL6) is a proto-oncogene that is highly expressed in acute lymphoblastic leukemia (ALL). BTB and CNC Homology 1 Basic Leucine Zipper Transcription Factor 2 (BACH2) is a suppressor of transcription. The BACH2–BCL6 balance controls selection at the pre-B cell receptor checkpoint by regulating p53 expression. However, the underlying mechanism and the clinical relevance of the BCL6/BACH2 axis are unknown. Here, we found that Ikaros, a tumor suppressor encoded by IKZF1, directly binds to both the BCL6 and BACH2 promoters where it suppresses BCL6 and promotes BACH2 expression in B-cell ALL (B-ALL) cells. Casein kinase 2 (CK2) inhibitors increase Ikaros function thereby inhibiting BCL6 and promoting BACH2 expression in an Ikaros-dependent manner. We also found that the expression of BCL6 is higher while BACH2 expression is lower in patients with B-ALL than normal bone marrow control. High BCL6 and low BACH2 expression is associated with high leukemic cell proliferation, unfavorable clinical and laboratory features, and inferior outcomes. Moreover, IKZF1 deletion is associated with high BCL6 and low BACH2 expression in B-ALL patients. CK2 inhibitors increase Ikaros binding to the promoter of BCL6 and BACH2 and suppress BCL6 while promoting BACH2 expression in the primary B-ALL cells. Our data indicates that Ikaros regulates expression of the BCL6/BACH2 axis in B-ALL. High BCL6 and low BACH2 expression are associated with Ikaros dysregulation and have a potential effect on the development of B-ALL.


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