Regulation of cellular proliferation in acute lymphoblastic leukemia by Casein Kinase II (CK2) and Ikaros.
The IKZF1 gene encodes the Ikaros protein, a zinc finger transcriptional factor that acts as a master regulator of hematopoiesis and a tumor suppressor in leukemia. Impaired activity of Ikaros is associated with the development of high-risk acute lymphoblastic leukemia (ALL) with a poor prognosis. The molecular mechanisms that regulate Ikaros' function as a tumor suppressor and regulator of cellular proliferation are not well understood. We demonstrated that Ikaros is a substrate for Casein Kinase II (CK2), an oncogenic kinase that is overexpressed in ALL. Phosphorylation of Ikaros by CK2 impairs Ikaros' DNA-binding ability, as well as Ikaros' ability to regulate gene expression and function as a tumor suppressor in leukemia. Targeting CK2 with specific inhibitors restores Ikaros' function as a transcriptional regulator and tumor suppressor resulting in a therapeutic, anti-leukemia effect in a preclinical model of ALL. Here, we review the genes and pathways that are regulated by Ikaros and the molecular mechanisms through which Ikaros and CK2 regulate cellular proliferation in leukemia.
Department of Pediatrics, Pennsylvania State University College of Medicine, Hershey, PA, 17033, USA.
Chandrika
C
Gowda
Department of Pediatrics, Pennsylvania State University College of Medicine, Hershey, PA, 17033, USA.
Chunhua
C
Song
Department of Pediatrics, Pennsylvania State University College of Medicine, Hershey, PA, 17033, USA.
Malika
M
Kapadia
Department of Pediatrics, Pennsylvania State University College of Medicine, Hershey, PA, 17033, USA; Loma Linda University, Loma Linda, CA, USA.
Jonathon L
JL
Payne
Department of Pediatrics, Pennsylvania State University College of Medicine, Hershey, PA, 17033, USA.
Tommy
T
Hu
Department of Pediatrics, Pennsylvania State University College of Medicine, Hershey, PA, 17033, USA.
Yali
Y
Ding
Department of Pediatrics, Pennsylvania State University College of Medicine, Hershey, PA, 17033, USA. Electronic address: sdovat@hmc.psu.edu.
Sinisa
S
Dovat
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D047390:Casein Kinase II / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000276:immunology; D002453:Cell Cycle / Q000187:drug effects / Q000235:genetics; D049109:Cell Proliferation / Q000187:drug effects; D002843:Chromatin / Q000737:chemistry / Q000187:drug effects / Q000276:immunology*; D042002:Chromatin Assembly and Disassembly / Q000187:drug effects; D004253:DNA Nucleotidylexotransferase / Q000235:genetics / Q000276:immunology; D005786:Gene Expression Regulation; D006801:Humans; D051740:Ikaros Transcription Factor / Q000235:genetics* / Q000276:immunology; D056484:Jumonji Domain-Containing Histone Demethylases / Q000235:genetics / Q000276:immunology; D009287:Naphthyridines / Q000494:pharmacology; D009687:Nuclear Proteins / Q000235:genetics / Q000276:immunology; D010619:Phenazines; D010766:Phosphorylation / Q000187:drug effects; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D012097:Repressor Proteins / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000473:pathology
D000970:Antineoplastic Agents; D002843:Chromatin; C497239:IKZF1 protein, human; D009287:Naphthyridines; D009687:Nuclear Proteins; D010619:Phenazines; D012097:Repressor Proteins; D051740:Ikaros Transcription Factor; C555142:silmitasertib; D056484:Jumonji Domain-Containing Histone Demethylases; C119611:KDM5B protein, human; D047390:Casein Kinase II; D004253:DNA Nucleotidylexotransferase
CX4945; Casein Kinase II (CK2); Ikaros; Leukemia; PP1; Phosphorylation; Protein phosphatase 1
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