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: Chunhua Song, Chandrika Gowda, Xiaokang Pan, Yali Ding, Yongqing Tong, Bi-Hua Tan, Haijun Wang, Sunil Muthusami, Zheng Ge, Mansi Sachdev, Shantu G Amin, Dhimant Desai, Krishne Gowda, Raghavendra Gowda, Gavin P Robertson, Hilde Schjerven, Markus Muschen, Kimberly J Payne, Sinisa Dovat
• Journal: Blood (Blood) Vol. 126 Issue 15 Pg. 1813-22 (Oct 08 2015) ISSN: 1528-0020 [Electronic] United States
• PMID: 26219304 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2015 by The American Society of Hematology.

Chemical References

• Enzyme Inhibitors
• RNA, Messenger
• Ikaros Transcription Factor
• Phosphatidylinositol 3-Kinases
• Casein Kinase II

Topics

• Animals
• Apoptosis (drug effects)
• Casein Kinase II (antagonists & inhibitors, genetics, metabolism)
• Cell Proliferation (drug effects)
• Chromatin Immunoprecipitation
• Enzyme Inhibitors (pharmacology)
• Female
• Genes, Tumor Suppressor
• Humans
• Ikaros Transcription Factor (genetics, metabolism)
• Mice
• Mice, Inbred NOD
• Phosphatidylinositol 3-Kinases
• Precursor B-Cell Lymphoblastic Leukemia-Lymphoma (drug therapy, metabolism, pathology)
• RNA, Messenger (genetics)
• Real-Time Polymerase Chain Reaction
• Reverse Transcriptase Polymerase Chain Reaction
• Signal Transduction (drug effects)
• Tumor Cells, Cultured
• Xenograft Model Antitumor Assays