TY - JOUR
T1 - Transcriptional regulation of JARID1B/KDM5B histone demethylase by ikaros, histone deacetylase 1 (HDAC1), and casein kinase 2 (CK2) in B-cell acute lymphoblastic leukemia
AU - Wang, Haijun
AU - Song, Chunhua
AU - Ding, Yali
AU - Pan, Xiaokang
AU - Ge, Zheng
AU - Tan, Bi Hua
AU - Gowda, Chandrika
AU - Sachdev, Mansi
AU - Muthusami, Sunil
AU - Ouyang, Hongsheng
AU - Lai, Liangxue
AU - Francis, Olivia L.
AU - Morris, Christopher L.
AU - Abdel-Azim, Hisham
AU - Dorsam, Glenn
AU - Xiang, Meixian
AU - Payne, Kimberly J.
AU - Dovat, Sinisa
N1 - Funding Information:
This work was supported by National Institutes of Health (NIH) Grant R01 HL095120, a St. Baldrick's Foundation Career Development Award, a Hyundai Hope on Wheels Scholar Grant Award, the Four Diamonds Fund of the Pennsylvania State University College of Medicine, and the John Wawrynovic Leukemia Research Scholar Endowment (to S. D.). This work was also supported by NIH grant R21CA162259, a St. Baldrick's Foundation Research Grant, a Hyundai Hope on Wheels Grant (to K. J. P.), the Department of Pathology and Human Anatomy, the Department of Basic Sciences (Grant to Promote Collaborative and Translational Research to K. J. P. and C. L. M.), and the Center for Health Disparities and Molecular Medicine (NIH Grant P20MD006988) at Loma Linda University School of Medicine. This work was supported in part by NIH Grant 1R15AI101968-01A1 (to G. P. D.) and by Natural Science Foundation of China Grant 31200264, Natural Science Foundation of Hubei Province Grant 2015BCA268, and "Chenguang Planning" from Natural Science Foundation of Wuhan City Grants 2015070404010201 and 2014070404010210 (to M. X.). The authors declare that they have no conflicts of interest with the contents of this article. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
PY - 2016/2/19
Y1 - 2016/2/19
N2 - Impaired function of the Ikaros (IKZF1) protein is associated with the development of high-risk B-cell precursor acute lymphoblastic leukemia (B-ALL). The mechanisms of Ikaros tumor suppressor activity in leukemia are unknown. Ikaros binds to the upstream regulatory elements of its target genes and regulates their transcription via chromatin remodeling. Here, we report that Ikaros represses transcription of the histone H3K4 demethylase, JARID1B (KDM5B). Transcriptional repression of JARID1B is associated with increased global levels of H3K4 trimethylation. Ikaros-mediated repression of JARID1B is dependent on the activity of the histone deacetylase, HDAC1, which binds to the upstream regulatory element of JARID1B in complex with Ikaros. In leukemia, JARID1B is overexpressed, and its inhibition results in cellular growth arrest. Ikaros-mediated repression of JARID1B in leukemia is impaired by pro-oncogenic casein kinase 2 (CK2). Inhibition of CK2 results in increased binding of the Ikaros-HDAC1 complex to the promoter of JARID1B, with increased formation of trimethylated histone H3 lysine 27 and decreased histone H3 Lys-9 acetylation. In cases of high-risk B-ALL that carry deletion of one Ikaros (IKZF1) allele, targeted inhibition of CK2 restores Ikaros binding to the JARID1B promoter and repression of JARID1B. In summary, the presented data suggest a mechanism through which Ikaros and HDAC1 regulate the epigenetic signature in leukemia: via regulation of JARID1B transcription. The presented data identify JARID1B as a novel therapeutic target in B-ALL and provide a rationale for the use of CK2 inhibitors in the treatment of high-risk B-ALL.
AB - Impaired function of the Ikaros (IKZF1) protein is associated with the development of high-risk B-cell precursor acute lymphoblastic leukemia (B-ALL). The mechanisms of Ikaros tumor suppressor activity in leukemia are unknown. Ikaros binds to the upstream regulatory elements of its target genes and regulates their transcription via chromatin remodeling. Here, we report that Ikaros represses transcription of the histone H3K4 demethylase, JARID1B (KDM5B). Transcriptional repression of JARID1B is associated with increased global levels of H3K4 trimethylation. Ikaros-mediated repression of JARID1B is dependent on the activity of the histone deacetylase, HDAC1, which binds to the upstream regulatory element of JARID1B in complex with Ikaros. In leukemia, JARID1B is overexpressed, and its inhibition results in cellular growth arrest. Ikaros-mediated repression of JARID1B in leukemia is impaired by pro-oncogenic casein kinase 2 (CK2). Inhibition of CK2 results in increased binding of the Ikaros-HDAC1 complex to the promoter of JARID1B, with increased formation of trimethylated histone H3 lysine 27 and decreased histone H3 Lys-9 acetylation. In cases of high-risk B-ALL that carry deletion of one Ikaros (IKZF1) allele, targeted inhibition of CK2 restores Ikaros binding to the JARID1B promoter and repression of JARID1B. In summary, the presented data suggest a mechanism through which Ikaros and HDAC1 regulate the epigenetic signature in leukemia: via regulation of JARID1B transcription. The presented data identify JARID1B as a novel therapeutic target in B-ALL and provide a rationale for the use of CK2 inhibitors in the treatment of high-risk B-ALL.
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U2 - 10.1074/jbc.M115.679332
DO - 10.1074/jbc.M115.679332
M3 - Article
C2 - 26655717
AN - SCOPUS:84962409485
SN - 0021-9258
VL - 291
SP - 4004
EP - 4018
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 8
ER -