Cellular signaling and epigenetic regulation of gene expression in leukemia

Chandrika Gowda, Chunhua Song, Yali Ding, Soumya Iyer, Pavan Dhanyamraju, Mary McGrath, Yevgeniya Bamme, Mario Soliman, Shriya Kane, Jonathon L. Payne, Sinisa Dovat

Research output: Contribution to journalReview article

Abstract

Alterations in normal regulation of gene expression is one of the key features of hematopoietic malignancies. In order to gain insight into the mechanisms that regulate gene expression in these diseases, we dissected the role of the Ikaros protein in leukemia. Ikaros is a DNA-binding, zinc finger protein that functions as a transcriptional regulator and a tumor suppressor in leukemia. The use of ChIP-seq, RNA-seq, and ATAC-seq—coupled with functional experiments—revealed that Ikaros regulates both the global epigenomic landscape and epigenetic signature at promoter regions of its target genes. Casein kinase II (CK2), an oncogenic kinase that is overexpressed in leukemia, directly phosphorylates Ikaros at multiple, evolutionarily-conserved residues. Phosphorylation of Ikaros impairs the protein's ability to regulate both the transcription of its target genes and global epigenetic landscape in leukemia. Treatment of leukemia cells with a specific inhibitor of CK2 restores Ikaros function, resulting in cytotoxicity of leukemia cells. Here, we review the mechanisms through which the CK2-Ikaros signaling axis regulates the global epigenomic landscape and expression of genes that control cellular proliferation in leukemia.

Original languageEnglish (US)
Article number100665
JournalAdvances in Biological Regulation
DOIs
StateAccepted/In press - Jan 1 2019

Fingerprint

Gene Expression Regulation
Epigenomics
Leukemia
Ikaros Transcription Factor
Gene Expression
Casein Kinase II
Zinc Fingers
Hematologic Neoplasms
Genetic Promoter Regions
Genes
Phosphotransferases
Phosphorylation
Cell Proliferation
RNA
DNA
Neoplasms

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Molecular Biology
  • Genetics
  • Cancer Research

Cite this

Gowda, Chandrika ; Song, Chunhua ; Ding, Yali ; Iyer, Soumya ; Dhanyamraju, Pavan ; McGrath, Mary ; Bamme, Yevgeniya ; Soliman, Mario ; Kane, Shriya ; Payne, Jonathon L. ; Dovat, Sinisa. / Cellular signaling and epigenetic regulation of gene expression in leukemia. In: Advances in Biological Regulation. 2019.
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Cellular signaling and epigenetic regulation of gene expression in leukemia. / Gowda, Chandrika; Song, Chunhua; Ding, Yali; Iyer, Soumya; Dhanyamraju, Pavan; McGrath, Mary; Bamme, Yevgeniya; Soliman, Mario; Kane, Shriya; Payne, Jonathon L.; Dovat, Sinisa.

In: Advances in Biological Regulation, 01.01.2019.

Research output: Contribution to journalReview article

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AU - Gowda, Chandrika

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AU - Ding, Yali

AU - Iyer, Soumya

AU - Dhanyamraju, Pavan

AU - McGrath, Mary

AU - Bamme, Yevgeniya

AU - Soliman, Mario

AU - Kane, Shriya

AU - Payne, Jonathon L.

AU - Dovat, Sinisa

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N2 - Alterations in normal regulation of gene expression is one of the key features of hematopoietic malignancies. In order to gain insight into the mechanisms that regulate gene expression in these diseases, we dissected the role of the Ikaros protein in leukemia. Ikaros is a DNA-binding, zinc finger protein that functions as a transcriptional regulator and a tumor suppressor in leukemia. The use of ChIP-seq, RNA-seq, and ATAC-seq—coupled with functional experiments—revealed that Ikaros regulates both the global epigenomic landscape and epigenetic signature at promoter regions of its target genes. Casein kinase II (CK2), an oncogenic kinase that is overexpressed in leukemia, directly phosphorylates Ikaros at multiple, evolutionarily-conserved residues. Phosphorylation of Ikaros impairs the protein's ability to regulate both the transcription of its target genes and global epigenetic landscape in leukemia. Treatment of leukemia cells with a specific inhibitor of CK2 restores Ikaros function, resulting in cytotoxicity of leukemia cells. Here, we review the mechanisms through which the CK2-Ikaros signaling axis regulates the global epigenomic landscape and expression of genes that control cellular proliferation in leukemia.

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