Transcriptional regulation of JARID1B/KDM5B histone demethylase by ikaros, histone deacetylase 1 (HDAC1), and casein kinase 2 (CK2) in B-cell acute lymphoblastic leukemia

Haijun Wang, Chunhua Song, Yali Ding, Xiaokang Pan, Zheng Ge, Bi Hua Tan, Chandrika Gowda, Mansi Sachdev, Sunil Muthusami, Hongsheng Ouyang, Liangxue Lai, Olivia L. Francis, Christopher L. Morris, Hisham Abdel-Azim, Glenn Dorsam, Meixian Xiang, Kimberly J. Payne, Sinisa Dovat

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)4004-4018
Number of pages15
JournalJournal of Biological Chemistry
Volume291
Issue number8
DOIs
StatePublished - Feb 19 2016

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Histone Demethylases
Histone Deacetylase 1
Casein Kinase II
B-Lymphoid Precursor Cells
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Leukemia
B-Lymphocytes
Transcription
Cells
Histones
Histone Deacetylases
Ikaros Transcription Factor
Acetylation
Chromatin Assembly and Disassembly
Epigenomics
Lysine
Chromatin
Tumors
Genes
Alleles

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Wang, Haijun ; Song, Chunhua ; Ding, Yali ; Pan, Xiaokang ; Ge, Zheng ; Tan, Bi Hua ; Gowda, Chandrika ; Sachdev, Mansi ; Muthusami, Sunil ; Ouyang, Hongsheng ; Lai, Liangxue ; Francis, Olivia L. ; Morris, Christopher L. ; Abdel-Azim, Hisham ; Dorsam, Glenn ; Xiang, Meixian ; Payne, Kimberly J. ; Dovat, Sinisa. / Transcriptional regulation of JARID1B/KDM5B histone demethylase by ikaros, histone deacetylase 1 (HDAC1), and casein kinase 2 (CK2) in B-cell acute lymphoblastic leukemia. In: Journal of Biological Chemistry. 2016 ; Vol. 291, No. 8. pp. 4004-4018.
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title = "Transcriptional regulation of JARID1B/KDM5B histone demethylase by ikaros, histone deacetylase 1 (HDAC1), and casein kinase 2 (CK2) in B-cell acute lymphoblastic leukemia",
abstract = "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.",
author = "Haijun Wang and Chunhua Song and Yali Ding and Xiaokang Pan and Zheng Ge and Tan, {Bi Hua} and Chandrika Gowda and Mansi Sachdev and Sunil Muthusami and Hongsheng Ouyang and Liangxue Lai and Francis, {Olivia L.} and Morris, {Christopher L.} and Hisham Abdel-Azim and Glenn Dorsam and Meixian Xiang and Payne, {Kimberly J.} and Sinisa Dovat",
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Wang, H, Song, C, Ding, Y, Pan, X, Ge, Z, Tan, BH, Gowda, C, Sachdev, M, Muthusami, S, Ouyang, H, Lai, L, Francis, OL, Morris, CL, Abdel-Azim, H, Dorsam, G, Xiang, M, Payne, KJ & Dovat, S 2016, 'Transcriptional regulation of JARID1B/KDM5B histone demethylase by ikaros, histone deacetylase 1 (HDAC1), and casein kinase 2 (CK2) in B-cell acute lymphoblastic leukemia', Journal of Biological Chemistry, vol. 291, no. 8, pp. 4004-4018. https://doi.org/10.1074/jbc.M115.679332

Transcriptional regulation of JARID1B/KDM5B histone demethylase by ikaros, histone deacetylase 1 (HDAC1), and casein kinase 2 (CK2) in B-cell acute lymphoblastic leukemia. / Wang, Haijun; Song, Chunhua; Ding, Yali; Pan, Xiaokang; Ge, Zheng; Tan, Bi Hua; Gowda, Chandrika; Sachdev, Mansi; Muthusami, Sunil; Ouyang, Hongsheng; Lai, Liangxue; Francis, Olivia L.; Morris, Christopher L.; Abdel-Azim, Hisham; Dorsam, Glenn; Xiang, Meixian; Payne, Kimberly J.; Dovat, Sinisa.

In: Journal of Biological Chemistry, Vol. 291, No. 8, 19.02.2016, p. 4004-4018.

Research output: Contribution to journalArticle

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

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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