Aberrant ARID5B expression and its association with Ikaros dysfunction in acute lymphoblastic leukemia

Zheng Ge,Kimberly J Payne,Qi Han,Qinyu Ge,Laszlo Szekely,Guofeng Gao,Yan Gu,Jinlong Ma,Chunhua Song,Sinisa Dovat,Justin Sloane

doi:10.1038/s41389-018-0095-x

Abstract

Mutations and single nucleotide polymorphisms of AT-rich interactive domain-containing protein 5B (ARID5B) are involved in the oncogenesis of acute lymphoblastic leukemia (ALL) and treatment outcomes. However, ARID5B expression and clinical significance in ALL remain unclear. We found ARID5B is significantly down-regulated in ALL compared to healthy bone marrow controls. ARID5B also interacts with PHD finger protein 2 (PHF2). Low expression of ARID5B (ARID5Blow) or ARID5B and PHF2 (ARID5BlowPHF2low) is correlated with the markers of cell proliferation and poor prognosis in ALL patients. Ikaros directly regulates ARID5B expression in ALL. Restoring Ikaros function by Casein Kinase II inhibition also promotes ARID5B expression through recruitment of trimethylation of lysine 4 on histone H3 (H3K4me3) at its promoter region. In summary, our data show that aberrant expression of ARID5B and PHF2 is related to leukemic cell proliferation and several poor prognostic markers. Our data indicate ARID5Blow expression, particularly ARID5BlowPHF2low expression, is linked to Ikaros dysfunction and involved in the oncogenic effect of high-risk ALL, which may represent a high-risk subgroup of ALL.

Highlights

Introduction The complex ofAT-rich interactive domain-containing protein 5B (ARID5B) formed with PHD finger protein 2 (PHF2) induces the demethylation of lysine 9 dimethylation on histone H3 (H3K9me2) to activate the transcription of the target genes[1,2]
We discovered that B-acute lymphoblastic leukemia (ALL) patients with low ARID5B expression represented a cohort with a significantly higher percentage of those requiring more than 4 weeks to reach complete remission (CR), a poor prognostic indicator in ALL, (51.4% vs. 16.0%, P = 0.002), as compared to that with high ARID5B expression (Table S1)
We found that ARID5B mRNA levels were positively correlated with PHF2 expression in the microarray analysis of

Summary

Introduction

Introduction The complex ofAT-rich interactive domain-containing protein 5B (ARID5B) formed with PHD finger protein 2 (PHF2) induces the demethylation of lysine 9 dimethylation on histone H3 (H3K9me2) to activate the transcription of the target genes[1,2]. ARID5B is widely expressed throughout the human body. ARID5B dysfunction appears to be closely linked with leukemia[2,3,4,5,6,7,8,9,10]. ARID5B mutations /SNPs (single nucleotide polymorphisms) are reported to be involved in the oncogenesis of acute lymphoblastic leukemia (ALL) and treatment outcome[3,4,5,6,7,8,9,10]. Reports showed that ARID5B knockdown impairs cell cycling by up-regulating p21, and contributes to methotrexate (MTX) and 6-. We observed that PHF2 expression is downregulated in ALL cells. The clinical significance of ARID5B expression has not been determined in ALL patients

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