title: Targeting casein kinase II restores Ikaros tumor suppressor activity and demonstrates therapeutic efficacy in high-risk leukemia.
abstract: Ikaros (IKZF1) is a tumor suppressor that binds DNA and regulates expression of its target genes. The mechanism of Ikaros activity as a tumor suppressor and the regulation of Ikaros function in leukemia are unknown. Here, we demonstrate that Ikaros controls cellular proliferation by repressing expression of genes that promote cell cycle progression and the phosphatidylinositol-3 kinase (PI3K) pathway. We show that Ikaros function is impaired by the pro-oncogenic casein kinase II (CK2), and that CK2 is overexpressed in leukemia. CK2 inhibition restores Ikaros function as transcriptional repressor of cell cycle and PI3K pathway genes, resulting in an antileukemia effect. In high-risk leukemia where one IKZF1 allele has been deleted, CK2 inhibition restores the transcriptional repressor function of the remaining wild-type IKZF1 allele. CK2 inhibition demonstrated a potent therapeutic effect in a panel of patient-derived primary high-risk B-cell acute lymphoblastic leukemia xenografts as indicated by prolonged survival and a reduction of leukemia burden. We demonstrate the efficacy of a novel therapeutic approach for high-risk leukemia: restoration of Ikaros tumor suppressor activity via inhibition of CK2. These results provide a rationale for the use of CK2 inhibitors in clinical trials for high-risk leukemia, including cases with deletion of one IKZF1 allele.
authors.affiliation: Department of Pediatrics, Pennsylvania State University College of Medicine, Hershey, PA;
authors.forename: Chunhua
authors.initials: C
authors.lastname: Song
authors.affiliation: Department of Pediatrics, Pennsylvania State University College of Medicine, Hershey, PA;
authors.forename: Chandrika
authors.initials: C
authors.lastname: Gowda
authors.affiliation: Department of Pediatrics, Pennsylvania State University College of Medicine, Hershey, PA;
authors.forename: Xiaokang
authors.initials: X
authors.lastname: Pan
authors.affiliation: Department of Pediatrics, Pennsylvania State University College of Medicine, Hershey, PA;
authors.forename: Yali
authors.initials: Y
authors.lastname: Ding
authors.affiliation: Department of Pediatrics, Pennsylvania State University College of Medicine, Hershey, PA;
authors.forename: Yongqing
authors.initials: Y
authors.lastname: Tong
authors.affiliation: Department of Pediatrics, Pennsylvania State University College of Medicine, Hershey, PA;
authors.forename: Bi-Hua
authors.initials: BH
authors.lastname: Tan
authors.affiliation: Department of Pediatrics, Pennsylvania State University College of Medicine, Hershey, PA;
authors.forename: Haijun
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Pediatrics, Pennsylvania State University College of Medicine, Hershey, PA;
authors.forename: Sunil
authors.initials: S
authors.lastname: Muthusami
authors.affiliation: Department of Pediatrics, Pennsylvania State University College of Medicine, Hershey, PA; Department of Hematology, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing, China;
authors.forename: Zheng
authors.initials: Z
authors.lastname: Ge
authors.affiliation: Department of Pediatrics, Pennsylvania State University College of Medicine, Hershey, PA;
authors.forename: Mansi
authors.initials: M
authors.lastname: Sachdev
authors.affiliation: Department of Pharmacology, Pennsylvania State University College of Medicine, Hershey, PA;
authors.forename: Shantu G
authors.initials: SG
authors.lastname: Amin
authors.affiliation: Department of Pharmacology, Pennsylvania State University College of Medicine, Hershey, PA;
authors.forename: Dhimant
authors.initials: D
authors.lastname: Desai
authors.affiliation: Department of Pharmacology, Pennsylvania State University College of Medicine, Hershey, PA;
authors.forename: Krishne
authors.initials: K
authors.lastname: Gowda
authors.affiliation: Department of Pharmacology, Pennsylvania State University College of Medicine, Hershey, PA;
authors.forename: Raghavendra
authors.initials: R
authors.lastname: Gowda
authors.affiliation: Department of Pharmacology, Pennsylvania State University College of Medicine, Hershey, PA;
authors.forename: Gavin P
authors.initials: GP
authors.lastname: Robertson
authors.affiliation: Department of Laboratory Medicine, University of California, San Francisco, San Francisco, CA; and.
authors.forename: Hilde
authors.initials: H
authors.lastname: Schjerven
authors.affiliation: Department of Laboratory Medicine, University of California, San Francisco, San Francisco, CA; and.
authors.forename: Markus
authors.initials: M
authors.lastname: Muschen
authors.affiliation: Department of Pathology and Human Anatomy, Loma Linda University, Loma Linda, CA.
authors.forename: Kimberly J
authors.initials: KJ
authors.lastname: Payne
authors.affiliation: Department of Pediatrics, Pennsylvania State University College of Medicine, Hershey, PA;
authors.forename: Sinisa
authors.identifier: http://orcid.org/0000-0003-3906-6165
authors.initials: S
authors.lastname: Dovat
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D047390:Casein Kinase II / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D047369:Chromatin Immunoprecipitation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D016147:Genes, Tumor Suppressor; D006801:Humans; D051740:Ikaros Transcription Factor / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D016688:Mice, Inbred NOD; D019869:Phosphatidylinositol 3-Kinases; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D004791:Enzyme Inhibitors; D012333:RNA, Messenger; D051740:Ikaros Transcription Factor; D019869:Phosphatidylinositol 3-Kinases; D047390:Casein Kinase II