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.
authors.affiliation: From the Department of Pathology, Xinxiang Medical University, Xinxiang 453003, Henan, China, Pennsylvania State University College of Medicine, Hershey, Pennsylvania 17033.
authors.forename: Haijun
authors.initials: H
authors.lastname: Wang
authors.affiliation: Pennsylvania State University College of Medicine, Hershey, Pennsylvania 17033.
authors.forename: Chunhua
authors.initials: C
authors.lastname: Song
authors.affiliation: Pennsylvania State University College of Medicine, Hershey, Pennsylvania 17033.
authors.forename: Yali
authors.initials: Y
authors.lastname: Ding
authors.affiliation: Pennsylvania State University College of Medicine, Hershey, Pennsylvania 17033.
authors.forename: Xiaokang
authors.initials: X
authors.lastname: Pan
authors.affiliation: Pennsylvania State University College of Medicine, Hershey, Pennsylvania 17033.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Ge
authors.affiliation: Pennsylvania State University College of Medicine, Hershey, Pennsylvania 17033.
authors.forename: Bi-Hua
authors.initials: BH
authors.lastname: Tan
authors.affiliation: Pennsylvania State University College of Medicine, Hershey, Pennsylvania 17033.
authors.forename: Chandrika
authors.initials: C
authors.lastname: Gowda
authors.affiliation: Pennsylvania State University College of Medicine, Hershey, Pennsylvania 17033.
authors.forename: Mansi
authors.initials: M
authors.lastname: Sachdev
authors.affiliation: Pennsylvania State University College of Medicine, Hershey, Pennsylvania 17033.
authors.forename: Sunil
authors.initials: S
authors.lastname: Muthusami
authors.affiliation: From the Department of Pathology, Xinxiang Medical University, Xinxiang 453003, Henan, China.
authors.forename: Hongsheng
authors.initials: H
authors.lastname: Ouyang
authors.affiliation: From the Department of Pathology, Xinxiang Medical University, Xinxiang 453003, Henan, China.
authors.forename: Liangxue
authors.initials: L
authors.lastname: Lai
authors.affiliation: Loma Linda University, Loma Linda, California 92350.
authors.forename: Olivia L
authors.initials: OL
authors.lastname: Francis
authors.affiliation: Loma Linda University, Loma Linda, California 92350.
authors.forename: Christopher L
authors.initials: CL
authors.lastname: Morris
authors.affiliation: the Division of Hematology, Oncology, and Blood and Marrow Transplantation, Children's Hospital Los Angeles, University of Southern California Keck School of Medicine, Los Angeles, California 90027.
authors.forename: Hisham
authors.initials: H
authors.lastname: Abdel-Azim
authors.affiliation: North Dakota State University, Fargo, North Dakota 58108, and.
authors.forename: Glenn
authors.initials: G
authors.lastname: Dorsam
authors.affiliation: the College of Pharmacy, South-Central University for Nationalities, Wuhan 430074, China.
authors.forename: Meixian
authors.initials: M
authors.lastname: Xiang
authors.affiliation: Loma Linda University, Loma Linda, California 92350.
authors.forename: Kimberly J
authors.initials: KJ
authors.lastname: Payne
authors.affiliation: Pennsylvania State University College of Medicine, Hershey, Pennsylvania 17033, sdovat@hmc.psu.edu.
authors.forename: Sinisa
authors.initials: S
authors.lastname: Dovat
mesh_terms: D047390:Casein Kinase II / Q000235:genetics / Q000378:metabolism*; D044127:Epigenesis, Genetic; D015971:Gene Expression Regulation, Enzymologic; D015973:Gene Expression Regulation, Leukemic; D056284:Histone Deacetylase 1 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051740:Ikaros Transcription Factor / Q000235:genetics / Q000378:metabolism*; D056484:Jumonji Domain-Containing Histone Demethylases / Q000096:biosynthesis* / Q000235:genetics; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D009687:Nuclear Proteins / Q000096:biosynthesis* / Q000235:genetics; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma; D012097:Repressor Proteins / Q000096:biosynthesis* / Q000235:genetics; D014158:Transcription, Genetic; D020298:U937 Cells
chemical_list: C497239:IKZF1 protein, human; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D012097:Repressor Proteins; D051740:Ikaros Transcription Factor; D056484:Jumonji Domain-Containing Histone Demethylases; C119611:KDM5B protein, human; D047390:Casein Kinase II; C110550:HDAC1 protein, human; D056284:Histone Deacetylase 1
keywords: ck2; hematopoiesis; ikzf1; lymphocyte; signal transduction; transcription regulation; transcription repressor; tumor suppressor gene