TY - JOUR
T1 - Cellular signaling and epigenetic regulation of gene expression in leukemia
AU - Gowda, Chandrika
AU - Song, Chunhua
AU - Ding, Yali
AU - Iyer, Soumya
AU - Dhanyamraju, Pavan K.
AU - McGrath, Mary
AU - Bamme, Yevgeniya
AU - Soliman, Mario
AU - Kane, Shriya
AU - Payne, Jonathon L.
AU - Dovat, Sinisa
N1 - Funding Information:
This work was supported by National Institutes of Health R01CA209829 (KJP and SD); R01CA213912 (SD and CS); F30CA221109 (JLP); Penn State Clinical and Translational Sciences KL2 award ( KL2 TR002015 ) to CG; Hyundai Hope on Wheels Scholar Grant (SD) and Young investigator award (CG), Four Diamonds Fund of the Pennsylvania State University College of Medicine (to SD, CG and CS); Bear Necessities Pediatric Cancer Foundation , Alex’s Lemonade Stand Foundation , and the John Wawrynovic Leukemia Research Scholar Endowment (to SD); and the St. Baldrick's Foundation (SD) career development award (CG) and summer fellowship award (SK) and Bear Necessities (CG); Rally foundation YI award (CG).
Publisher Copyright:
© 2019 The Authors
PY - 2020/1
Y1 - 2020/1
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.
AB - 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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U2 - 10.1016/j.jbior.2019.100665
DO - 10.1016/j.jbior.2019.100665
M3 - Review article
C2 - 31623972
AN - SCOPUS:85073545516
VL - 75
JO - Advances in Biological Regulation
JF - Advances in Biological Regulation
SN - 2212-4926
M1 - 100665
ER -