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Blood. 2015 Oct 8;126(15):1813-22. doi: 10.1182/blood-2015-06-651505. Epub 2015 Jul 28.

Targeting casein kinase II restores Ikaros tumor suppressor activity and demonstrates therapeutic efficacy in high-risk leukemia.

Author information

1
Department of Pediatrics, Pennsylvania State University College of Medicine, Hershey, PA;
2
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;
3
Department of Pharmacology, Pennsylvania State University College of Medicine, Hershey, PA;
4
Department of Laboratory Medicine, University of California, San Francisco, San Francisco, CA; and.
5
Department of Pathology and Human Anatomy, Loma Linda University, Loma Linda, CA.

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.

PMID:
26219304
PMCID:
PMC4600018
DOI:
10.1182/blood-2015-06-651505
[Indexed for MEDLINE]
Free PMC Article

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