Targeting CK2 overexpression and hyperactivation as a novel therapeutic tool in chronic lymphocytic leukemia

• Published in: Blood Vol. 116; no. 15; pp. 2724 - 2731
• Main Authors: Martins, Leila R., Lúcio, Paulo, Silva, Milene C., Anderes, Kenna L., Gameiro, Paula, Silva, Maria G., Barata, João T.
• Format: Journal Article
• Language: English
• Published: Washington, DC Elsevier Inc 14-10-2010; Americain Society of Hematology
• Subjects: 1-Phosphatidylinositol 3-kinase; Adult; Aged; Aged, 80 and over; Apoptosis - drug effects; Apoptosis - physiology; B-Lymphocytes - drug effects; Biological and medical sciences; Case-Control Studies; Casein Kinase II - antagonists & inhibitors; Casein Kinase II - genetics; Casein Kinase II - metabolism; Cell Survival - drug effects; Cell Survival - physiology; Enzyme Activation; Female; Gene Expression; Hematologic and hematopoietic diseases; Humans; In Vitro Techniques; Leukemia, Lymphocytic, Chronic, B-Cell - drug therapy; Leukemia, Lymphocytic, Chronic, B-Cell - enzymology; Leukemia, Lymphocytic, Chronic, B-Cell - genetics; Leukemia, Lymphocytic, Chronic, B-Cell - pathology; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Male; Medical sciences; Middle Aged; Protein Kinase Inhibitors - pharmacology; PTEN Phosphohydrolase - metabolism; RNA, Small Interfering - genetics; T-Lymphocytes - drug effects; Chronic lymphocytic leukemia; Treatment; Targeting; Hematology; Lymphoproliferative syndrome; Gene overexpression; Malignant hemopathy; Casein kinase II; Cancer
• ISSN: 0006-4971; 1528-0020; 1528-0020
• DOI: 10.1182/blood-2010-04-277947

Expression of protein kinase CK2 is frequently deregulated in cancer and mounting evidence implicates CK2 in tumorigenesis. Here, we show that CK2 is overexpressed and hyperactivated in chronic lymphocytic leukemia (CLL). Inhibition of CK2 induces apoptosis of CLL cells without significantly affecting normal B and T lymphocytes. Importantly, this effect is not reversed by coculture with OP9 stromal cells, which are otherwise capable of rescuing CLL cells from in vitro spontaneous apoptosis. CLL cell death upon CK2 inhibition is mediated by inactivation of PKC, a PI3K downstream target, and correlates with increased PTEN activity, indicating that CK2 promotes CLL cell survival at least in part via PI3K-dependent signaling. Although CK2 antagonists induce significant apoptosis of CLL cells in all patient samples analyzed, sensitivity to CK2 blockade positively correlates with the percentage of CLL cells in the peripheral blood, β2 microglobulin serum levels and clinical stage. These data suggest that subsets of patients with aggressive and advanced stage disease may especially benefit from therapeutic strategies targeting CK2 function. Overall, our study indicates that CK2 plays a critical role in CLL cell survival, laying the groundwork for the inclusion of CK2 inhibitors into future therapeutic strategies.