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

Abstract

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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