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Protein Kinase CK2 as an Unfavorable Prognostic Marker and Novel Therapeutic Target in Acute Myeloid Leukemia

Authors' Affiliation: Department of Internal Medicine, Brain Korea 21 Research Team of Nanobiomaterials for the Cell-Based Implants, Medical Research Center, Department of Pathology, Yonsei University College of Medicine, Seoul, Korea

Requests for reprints: Yoo Hong Min, Department of Internal Medicine, Yonsei University College of Medicine, Seodaemun-ku, Shinchon-dong 134, Seoul 120-752, Korea. Phone: 82-2-2228-1956; Fax: 82-2-393-6884; E-mail: minbrmmd{at}yumc.yonsei.ac.kr.

Introduction: Protein kinase CK2 is implicated in cellular proliferation and transformation. However, the clinical and biological significances of CK2 have not been elucidated in acute myeloid leukemia (AML).

Experimental Design: We evaluated the biological significances of catalytic subunit of CK2 (CK2) expression in leukemia cell lines and primary leukemic blasts obtained from AML patients.

Results: In this study, the expression of CK2 was elevated in a substantial proportion of AML. In AML patients with normal karyotype, the disease-free survival and overall survival rates were significantly lower in the CK2-high compared with the CK2-low AML cases (P = 0.0252 and P = 0.0392, respectively). An induced overexpression of CK2 increased the levels of Ser⁴⁷³ phosphorylated (p)-Akt/protein kinase B (PKB), p-PDK1, pFKHR, p-BAD, Bcl-2, Bcl-xL, Mcl-1, and XIAP. Treatment of U937 cell line and primary AML blasts with selective CK2 inhibitor, tetrabromobenzotriazole or apigenin, reduced the levels of these molecules in a dose-dependent manner. CK2 small interfering RNA treatment also resulted in a down-regulation of p-Akt/PKB and Bcl-2 in U937 cells. Apigenin-induced cell death was preferentially observed in the CK2-high leukemia cell lines, HL-60 and NB4, which was accompanied by cytoplasmic release of SMAC/DIABLO and proteolytic cleavage of procaspase-9, procaspase-3, procaspase-8, and poly(ADP)ribose polymerase. An induced overexpression of CK2 potentially enhanced the sensitivity of U937 cells to the apigenin-induced cell death. Apigenin-induced cell death was significantly higher in CK2-high AML compared with CK2-low AML (P < 0.0001) or normal bone marrow samples (P < 0.0001).

Conclusion: These findings strongly suggest protein kinase CK2 as an unfavorable prognostic marker and novel therapeutic target in AML.