Oncotarget

Research Papers:

High CRLF2 expression associates with IKZF1 dysfunction in adult acute lymphoblastic leukemia without CRLF2 rearrangement

Zheng Ge, Yan Gu, Gang Zhao, Jianyong Li, Baoan Chen, Qi Han, Xing Guo, Juan Liu, Hui Li, Michael D. Yu, Justin Olson, Sadie Steffens, Kimberly J. Payne, Chunhua Song and Sinisa Dovat _

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Oncotarget. 2016; 7:49722-49732. https://doi.org/10.18632/oncotarget.10437

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Abstract

Zheng Ge1, Yan Gu2, Gang Zhao1, Jianyong Li2, Baoan Chen1, Qi Han2, Xing Guo2, Juan Liu2, Hui Li3, Michael D. Yu4, Justin Olson5, Sadie Steffens3, Kimberly J. Payne6, Chunhua Song3, Sinisa Dovat3

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

2Department of Hematology, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing, 210029, China

3Department of Pediatrics, Pennsylvania State University Medical College, Hershey, PA, 17033, USA

4Sydney Kimmel Medical College at Thomas Jefferson University, Philadelphia, PA, 19107 USA

5University of Wisconsin at Stout, Menomonie, WI, 54751, USA

6Loma Linda University, Department of Pathology and Human Anatomy, Loma Linda, CA, 92350, USA

Correspondence to:

Zheng Ge, email: Janege879@hotmail.com

Chunhua Song, email: csong@hmc.psu.edu

Sinisa Dovat, email: sdovat@hmc.psu.edu

Keywords: CRLF2, IKZF1, adult, acute lymphoblastic leukemia

Received: June 06, 2016     Accepted: June 24, 2016     Published: July 06, 2016

ABSTRACT

Overexpression of cytokine receptor-like factor 2 (CRLF2) due to chromosomal rearrangement has been observed in acute lymphoblastic leukemia (ALL) and reported to contribute to oncogenesis and unfavorable outcome in ALL. We studied B-ALL and T-ALL patients without CRLF2 rearrangement and observed that CRLF2 is significantly increased in a subset of these patients. Our study shows that high CRLF2expression correlates with high-risk ALL markers, as well as poor survival. We found that the IKZF1-encoded protein, Ikaros, directly binds to the CRLF2 promoter and regulates CRLF2 expression in leukemia cells. CK2 inhibitor, which can increase Ikaros activity, significantly increases Ikaros binding in ALL cells and suppresses CRLF2 expression in an Ikaros-dependent manner. CRLF2 expression is significantly higher in patients with IKZF1 deletion as compared to patients without IKZF1 deletion. Treatment with CK2 inhibitor also results in an increase in IKZF1 binding to the CRLF2 promoter and suppression of CRLF2 expression in primary ALL cells. We further observed that CK2 inhibitor induces increased H3K9me3 histone modifications in the CRLF2 promoter in ALL cell lines and primary cells. Taken together, our results demonstrate that high expression of CRLF2 correlates with high-risk ALL and short survival in patients without CRLF2 rearrangement. Our results are the first to demonstrate that the IKZF1-encoded Ikaros protein directly suppresses CRLF2 expression through enrichment of H3K9me3 in its promoter region. Our data also suggest that high CRLF2 expression works with the IKZF1 deletion to drive oncogenesis of ALL and has significance in an integrated prognostic model for adult high-risk ALL.


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