Department of Pediatrics, Pennsylvania State University College of Medicine, Hershey, PA, USA.
Department of Pediatrics, Pennsylvania State University College of Medicine, Hershey, PA, USA.
Adv Biol Regul. 2020 Jan;75:100665. doi: 10.1016/j.jbior.2019.100665. Epub 2019 Oct 5.
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.
正常的基因表达调控改变是血液系统恶性肿瘤的一个关键特征。为了深入了解这些疾病中调节基因表达的机制，我们剖析了 Ikaros 蛋白在白血病中的作用。Ikaros 是一种 DNA 结合的锌指蛋白，作为转录调节剂和白血病中的肿瘤抑制因子发挥作用。使用 ChIP-seq、RNA-seq 和 ATAC-seq 结合功能实验表明，Ikaros 调节其靶基因启动子区域的整体表观基因组景观和表观遗传特征。酪蛋白激酶 2（CK2）是一种在白血病中过度表达的致癌激酶，可直接在多个进化保守的残基上磷酸化 Ikaros。Ikaros 的磷酸化会损害其调节靶基因转录和白血病中全局表观基因组景观的能力。用 CK2 的特异性抑制剂处理白血病细胞可恢复 Ikaros 的功能，导致白血病细胞的细胞毒性。在这里，我们回顾了 CK2-Ikaros 信号轴调节控制白血病中细胞增殖的基因的全局表观基因组景观和表达的机制。
