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, Sinisa Dovat

Research output: Contribution to journalArticle

16 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)8022-8034
Number of pages13
JournalOncotarget
Volume8
Issue number5
DOIs
StatePublished - 2017

All Science Journal Classification (ASJC) codes

  • Oncology

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    Ge, Z., Zhou, X., Gu, Y., Han, Q., Li, J., Chen, B., Ge, Q., Dovat, E., Payne, J. L., Sun, T., Song, C., & Dovat, S. (2017). Ikaros regulation of the BCL6/BACH2 axis and its clinical relevance in acute lymphoblastic leukemia. Oncotarget, 8(5), 8022-8034. https://doi.org/10.18632/oncotarget.14038