Protein Kinase CK2α as an Unfavorable Prognostic Marker and Novel Therapeutic Target in Acute Myeloid Leukemia

Kim, Jin Seok; Eom, Ju In; Cheong, June Won; Choi, Ae Jin; Lee, Jin Koo; Yang, Woo Ick; Min, Yoo Hong

doi:10.1158/1078-0432.ccr-06-1602

Cited by 180 publications

(140 citation statements)

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“…In the study of Kim et al, 52 CK2a subunit expression was investigated in AML samples from patients. High CK2a levels were observed in a significant proportion of cases; however, CK2a was also expressed at lower levels in a subset of patients.…”

Section: Amlmentioning

confidence: 99%

Protein kinase CK2 in hematologic malignancies: reliance on a pivotal cell survival regulator by oncogenic signaling pathways

et al. 2012

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CK2 is a multitask kinase whose role is essential for a countless number of cellular processes, many of which are critical for blood cell development. A prevailing task for this kinase rests on counteracting programmed cell death triggered by multiple stimuli. CK2 is overexpressed in many solid tumors and in vivo mouse models have proven its tumorigenic potential. Recent data have suggested that CK2 may also have a significant role in the pathogenesis of hematopoietic tumors, such as multiple myeloma, chronic lymphocytic leukemia, acute myelogenous leukemia, acute lymphoblastic leukemia and chronic myeloproliferative neoplasms. CK2 regulates hematopoiesis-associated signaling pathways and seems to reinforce biochemical cascades indispensable for tumor growth, proliferation and resistance to conventional and novel cytotoxic agents. Although its activity is multifold, recent evidence supports the rationale of CK2 inhibition as a therapeutic strategy in solid and hematological tumors and phase-I clinical trials are in progress to test the efficacy of this innovative therapeutic approach. In this review, we will summarize the data supporting CK2 as an oncogenic kinase in blood tumors and we will describe some critical signaling pathways, whose regulation by this protein kinase may be implicated in tumorigenesis. Leukemia (2012Leukemia ( ) 26, 1174Leukemia ( --1179 doi:10.1038/leu.2011; published online 13 January 2012Keywords: hematopoiesis; blood tumors; protein kinase CK2; kinase inhibitors INTRODUCTION Protein kinase CK2 is a highly conserved pleiotropic acidophilic serine-threonine kinase whose essential role in several cellular processes has been increasingly appreciated over the last decade. 1 Structurally, CK2 is a tetrameric enzyme, composed by the assembly of two catalytic (a and/or a') and two regulatory b subunits. The catalytic and regulatory subunits may also be present in the cell as unassembled molecules and it seems that this state is associated with distinct and specific functions. The two catalytic subunits a and a' share 90% sequence homology in their N-terminal region. The regulatory subunit b instead does not have any similarity to the other two subunits. 2 CK2 recognizes motifs characterized by a S/T N-terminal to acidic amino acids, its minimum consensus being S/T-X-X-Ac, where X is any amino acid and Ac is a residue with a carboxylic or phosphorylated side chain (E, D, pS, pY).The spectrum of actions of this kinase is impressive as it can phosphorylate hundreds of substrate proteins, which are involved in disparate cellular processes, such as regulation of cell structure, division, proliferation, programmed death, DNA damage repair, protein translation, gene transcription, organelle function and so forth. 3 It has been estimated that a substantial proportion of the human phosphoproteome (up to 20%) is generated by CK2 alone. For this reason, CK2 has long been viewed as a 'non-targetable' kinase for therapeutic purposes.The essential role of CK2 for cell and organism life is underscored by th...

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Section: Amlmentioning

confidence: 99%

Protein kinase CK2 in hematologic malignancies: reliance on a pivotal cell survival regulator by oncogenic signaling pathways

et al. 2012

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“…Elevated level and prognostic significance of CK2α have been found in colorectal cancer (Pornchai et al, 2004), lung cancer (Lin et al, 2011), prostate cancer (Laramas et al, 2007) and leukemia (Kim et al, 2007). These findings support the idea that CK2α acts as a cancer driver.…”

Section: Discussionmentioning

confidence: 62%

Elevated Expression of Nuclear Protein Kinase CK2α as a Poor Prognosis Indicator in Lymph Node Cancerous Metastases of Human Thyroid Cancers

Guo¹,

Liu²,

Qi³

et al. 2014

Asian Pacific Journal of Cancer Prevention

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Aim: To investigate the expression of protein kinase CK2α (CK2α) in human thyroid disease and its relationship with thyroid cancer metastasis. Materials and Methods: Using immunohistochemistry we measured the expression of CK2α in 76 benign and malignant human thyroid cancer tissues, including 10 pairs of papillary carcinoma tissues with or without lymph node cancerous metastasis and similarly 10 pairs of lymph nodes. Results: The expression of CK2α was found to be higher in thyroid carcinoma cases (papillary carcinoma, follicular carcinoma, anaplastic carcinoma and medullary carcinoma) than in ones such as chronic lymphocytic thyroiditis, nodular goiter and adenoma. These findings were also confirmed by RT-PCR and Western blotting. More strikingly, elevated expression of CK2α in thyroid papillary carcinoma tissues was not only significantly associated with lymph node cancerous metastasis and clinical stage of thyroid cancers; but also correlated with epithelial-mesenchymal transition (EMT) and high tenascin C (TNC) expression. In addition, EMT and high TNC expression in thyroid carcinoma tissues was significantly associated with lymph node cancerous metastasis. Conclusions: Elevated expression of nuclear CK2α is a poor prognosis indicator in lymph node cancerous metastasis of human thyroid cancers.

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“…CK2 activity is increased in leukemia as compared with normal bone marrow (41,42). Because the results in Fig.…”

Section: Ck2 Inhibits Ikaros-mediated Repression Of Jarid1b-ourmentioning

confidence: 83%

Transcriptional Regulation of JARID1B/KDM5B Histone Demethylase by Ikaros, Histone Deacetylase 1 (HDAC1), and Casein Kinase 2 (CK2) in B-cell Acute Lymphoblastic Leukemia

Wang

Song

Ding

et al. 2016

Journal of Biological Chemistry

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Impaired function of the Ikaros (IKZF1) protein is associated with the development of high-risk B-cell precursor acute lymphoblastic leukemia (B-ALL). The mechanisms of Ikaros tumorsuppressor activity in leukemia are unknown. Ikaros binds to the upstream regulatory elements of its target genes and regulates their transcription via chromatin remodeling. Here, we report that Ikaros represses transcription of the histone H3K4 demethylase, JARID1B (KDM5B). Transcriptional repression of JARID1B is associated with increased global levels of H3K4 trimethylation. Ikaros-mediated repression of JARID1B is dependent on the activity of the histone deacetylase, HDAC1, which binds to the upstream regulatory element of JARID1B in complex with Ikaros. In leukemia, JARID1B is overexpressed, and its inhibition results in cellular growth arrest. Ikaros-mediated repression of JARID1B in leukemia is impaired by pro-oncogenic casein kinase 2 (CK2). Inhibition of CK2 results in increased binding of the Ikaros-HDAC1 complex to the promoter of JARID1B, with increased formation of trimethylated histone H3 lysine 27 and decreased histone H3 Lys-9 acetylation. In cases of high-risk B-ALL that carry deletion of one Ikaros (IKZF1) allele, targeted inhibition of CK2 restores Ikaros binding to the JARID1B promoter and repression of JARID1B. In summary, the presented data suggest a mechanism through which Ikaros and HDAC1 regulate the epigenetic signature in leukemia: via regulation of JARID1B transcription. The presented data identify JARID1B as a novel therapeutic target in B-ALL and provide a rationale for the use of CK2 inhibitors in the treatment of high-risk B-ALL.IKZF1 encodes the Ikaros DNA-binding zinc finger protein (1-4). Ikaros is essential for normal hematopoiesis and acts as a tumor suppressor (5, 6). In humans, deletion of a single Ikaros allele is associated with the development of high-risk B-cell precursor acute lymphoblastic leukemia (B-ALL) 3 that is characterized by resistance to chemotherapy and poor prognosis (7-9). Alterations in the Ikaros have also been associated with T cell ALL (10, 11) and myeloid leukemias (12-16). Ikaros regulates transcription of its target genes via chromatin remodeling (9). Ikaros has been shown to directly bind histone deacetylases HDAC1 and HDAC2 and to associate with the chromatin remodeling complex NuRD through interaction with the Mi-2 protein (9, 17).Ikaros is hypothesized to recruit chromatin remodeling complexes to the regulatory elements of its target genes, resulting in chromatin modifications (primarily histone deacetylation) and transcriptional repression or activation of its target genes (18 -20). Mechanisms of Ikaros-mediated repression that are independent of histone deacetylase have also been described (18, 3 The abbreviations used are: B-ALL, B-cell precursor acute lymphoblastic leukemia; CK2, casein kinase 2; TSS, transcriptional start site; ALL, acute lymphoblastic leukemia; TBB, 4,5,6,7-tetrabromobenzotriazole; IK haploid , Ikaros haploinsufficiency; Ikaros-CTS, C terminus o...

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Protein Kinase CK2α as an Unfavorable Prognostic Marker and Novel Therapeutic Target in Acute Myeloid Leukemia

Cited by 180 publications

References 61 publications

Protein kinase CK2 in hematologic malignancies: reliance on a pivotal cell survival regulator by oncogenic signaling pathways

Protein kinase CK2 in hematologic malignancies: reliance on a pivotal cell survival regulator by oncogenic signaling pathways

Elevated Expression of Nuclear Protein Kinase CK2α as a Poor Prognosis Indicator in Lymph Node Cancerous Metastases of Human Thyroid Cancers

Transcriptional Regulation of JARID1B/KDM5B Histone Demethylase by Ikaros, Histone Deacetylase 1 (HDAC1), and Casein Kinase 2 (CK2) in B-cell Acute Lymphoblastic Leukemia

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