Gowda Chandrika S, Song Chunhua, Ding Yali, Kapadia Malika, Dovat Sinisa
Department of Pediatrics, Penn State University College of Medicine, Hershey, Pennsylvania, USA.
J Investig Med. 2016 Mar;64(3):735-9. doi: 10.1136/jim-2016-000075. Epub 2016 Feb 9.
Protein signaling and regulation of gene expression are the two major mechanisms that regulate cellular proliferation in leukemia. Discerning the function of these processes is essential for understanding the pathogenesis of leukemia and for developing the targeted therapies. Here, we provide an overview of one of the mechanisms that regulates gene transcription in leukemia. This mechanism involves the direct interaction between Casein Kinase II (CK2) and the Ikaros transcription factor. Ikaros (IKZF1) functions as a master regulator of hematopoiesis and a tumor suppressor in acute lymphoblastic leukemia (ALL). Impaired Ikaros function results in the development of high-risk leukemia. Ikaros binds to the upstream regulatory elements of its target genes and regulates their transcription via chromatin remodeling. In vivo, Ikaros is a target for CK2, a pro-oncogenic kinase. CK2 directly phosphorylates Ikaros at multiple amino acids. Functional experiments showed that CK2-mediated phosphorylation of Ikaros, regulates Ikaros' DNA binding affinity, subcellular localization and protein stability. Recent studies revealed that phosphorylation of Ikaros by CK2 regulates Ikaros binding and repression of the terminal deoxytransferase (TdT) gene in normal thymocytes and in T-cell ALL. Available data suggest that the oncogenic activity of CK2 in leukemia involves functional inactivation of Ikaros and provide a rationale for CK2 inhibitors as a potential treatment for ALL.
蛋白质信号传导和基因表达调控是调节白血病细胞增殖的两个主要机制。辨别这些过程的功能对于理解白血病的发病机制和开发靶向治疗方法至关重要。在此，我们概述白血病中调节基因转录的机制之一。该机制涉及酪蛋白激酶II（CK2）与Ikaros转录因子之间的直接相互作用。Ikaros（IKZF1）在急性淋巴细胞白血病（ALL）中作为造血的主要调节因子和肿瘤抑制因子发挥作用。Ikaros功能受损会导致高危白血病的发生。Ikaros与其靶基因的上游调控元件结合，并通过染色质重塑调节其转录。在体内，Ikaros是原癌基因激酶CK2的作用靶点。CK2直接在多个氨基酸位点磷酸化Ikaros。功能实验表明，CK2介导的Ikaros磷酸化调节Ikaros的DNA结合亲和力、亚细胞定位和蛋白质稳定性。最近的研究表明，在正常胸腺细胞和T细胞ALL中，CK2对Ikaros的磷酸化调节Ikaros与末端脱氧转移酶（TdT）基因的结合及抑制作用。现有数据表明，CK2在白血病中的致癌活性涉及Ikaros的功能失活，并为CK2抑制剂作为ALL的潜在治疗方法提供了理论依据。
