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

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

doi:10.18632/oncotarget.10437

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.

Highlights

Cytokine receptor-like factor 2 (CRLF2), known as thymic stromal lymphopoietin (TSLP) receptor, is a type I cytokine receptor
IKZF1 deletion occurs in 43% of pediatric acute lymphoblastic leukemia (ALL) with cytokine receptor-like factor 2 (CRLF2) overexpression [11], it is present in ~80% of Ph-like ALL with CRLF2 rearrangement [13]
We found that the CRLF2 mRNA level is significantly higher in both B-ALL and T-ALL patients when compared to that of normal bone marrow controls (Figure 1A)

Summary

Introduction

Cytokine receptor-like factor 2 (CRLF2), known as thymic stromal lymphopoietin (TSLP) receptor, is a type I cytokine receptor. The CRLF2 subunit generates the functional receptor for TSLP by forming a heterodimeric complex with interleukin-7 receptor alpha (IL7Rα) [1]. Both the cytokine and its receptor have been implicated in tumorigenesis [2]. The CRLF2 rearrangement subtype is reported to account for only about half of ALL with high CRLF2 expression [11, 12]. IKZF1 deletion occurs in 43% of pediatric ALL with CRLF2 overexpression [11], it is present in ~80% of Ph-like ALL with CRLF2 rearrangement [13]. IKZF1 deletions and CRLF2 overexpression were identified in 12% and 11%, respectively, of Japanese Ph-like ALL patients, [7]. It is unknown whether CRLF2 is a direct target of IKZF1 or if IKZF1 deletion is associated with increased CRLF2 expression in ALL, in cases without CRLF2 rearrangement

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Conclusion