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

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

Research output: Contribution to journalArticlepeer-review

56 Scopus citations

Abstract

Ikaros (IKZF1) is a tumor suppressor that bindsDNAand 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.CK2inhibition 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.

Original languageEnglish (US)
Pages (from-to)1813-1822
Number of pages10
JournalBlood
Volume126
Issue number15
DOIs
StatePublished - Oct 8 2015

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

Fingerprint Dive into the research topics of 'Targeting casein kinase II restores Ikaros tumor suppressor activity and demonstrates therapeutic efficacy in high-risk leukemia'. Together they form a unique fingerprint.

Cite this