title: Protein kinase CK2 regulates AKT, NF-κB and STAT3 activation, stem cell viability and proliferation in acute myeloid leukemia.
abstract: Protein kinase CK2 sustains acute myeloid leukemia cell growth, but its role in leukemia stem cells is largely unknown. Here, we discovered that the CK2 catalytic α and regulatory β subunits are consistently expressed in leukemia stem cells isolated from acute myeloid leukemia patients and cell lines. CK2 inactivation with the selective inhibitor CX-4945 or RNA interference induced an accumulation of leukemia stem cells in the late S-G2-M phases of the cell cycle and triggered late-onset apoptosis. As a result, leukemia stem cells displayed an increased sensitivity to the chemotherapeutic agent doxorubicin. From a molecular standpoint, CK2 blockade was associated with a downmodulation of the stem cell-regulating protein BMI-1 and a marked impairment of AKT, nuclear factor-κB (NF-κB) and signal transducer and activator of transcription 3 (STAT3) activation, whereas FOXO3a nuclear activity was induced. Notably, combined CK2 and either NF-κB or STAT3 inhibition resulted in a superior cytotoxic effect on leukemia stem cells. This study suggests that CK2 blockade could be a rational approach to minimize the persistence of residual leukemia cells.
authors.affiliation: Department of Medicine, Division of Hematology, University of Padova, Padova, Italy.|Laboratory of Normal and Malignant Hematopoiesis, Venetian Institute of Molecular Medicine, Padova, Italy.
authors.forename: L
authors.initials: L
authors.lastname: Quotti Tubi
authors.affiliation: Department of Medicine, Division of Hematology, University of Padova, Padova, Italy.|Laboratory of Normal and Malignant Hematopoiesis, Venetian Institute of Molecular Medicine, Padova, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Canovas Nunes
authors.affiliation: Department of Medicine, Division of Hematology, University of Padova, Padova, Italy.|Laboratory of Normal and Malignant Hematopoiesis, Venetian Institute of Molecular Medicine, Padova, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Brancalion
authors.affiliation: Department of Medicine, Division of Hematology, University of Padova, Padova, Italy.|Laboratory of Normal and Malignant Hematopoiesis, Venetian Institute of Molecular Medicine, Padova, Italy.
authors.forename: E
authors.initials: E
authors.lastname: Doriguzzi Breatta
authors.affiliation: Department of Medicine, Division of Hematology, University of Padova, Padova, Italy.|Laboratory of Normal and Malignant Hematopoiesis, Venetian Institute of Molecular Medicine, Padova, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Manni
authors.affiliation: Department of Medicine, Division of Hematology, University of Padova, Padova, Italy.|Laboratory of Normal and Malignant Hematopoiesis, Venetian Institute of Molecular Medicine, Padova, Italy.
authors.forename: E
authors.initials: E
authors.lastname: Mandato
authors.affiliation: Department of Medicine, Division of Hematology, University of Padova, Padova, Italy.|Laboratory of Normal and Malignant Hematopoiesis, Venetian Institute of Molecular Medicine, Padova, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Zaffino
authors.affiliation: Department of Medicine, Division of Hematology, University of Padova, Padova, Italy.|Laboratory of Normal and Malignant Hematopoiesis, Venetian Institute of Molecular Medicine, Padova, Italy.
authors.forename: P
authors.initials: P
authors.lastname: Macaccaro
authors.affiliation: Department of Medicine, Division of Hematology, University of Padova, Padova, Italy.|Laboratory of Normal and Malignant Hematopoiesis, Venetian Institute of Molecular Medicine, Padova, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Carrino
authors.affiliation: Department of Medicine, Division of Hematology, University of Padova, Padova, Italy.|Laboratory of Normal and Malignant Hematopoiesis, Venetian Institute of Molecular Medicine, Padova, Italy.
authors.forename: K
authors.initials: K
authors.lastname: Gianesin
authors.affiliation: Department of Medicine, Division of Hematology, University of Padova, Padova, Italy.|Laboratory of Normal and Malignant Hematopoiesis, Venetian Institute of Molecular Medicine, Padova, Italy.
authors.forename: L
authors.initials: L
authors.lastname: Trentin
authors.affiliation: Department of Medicine, Division of Hematology, University of Padova, Padova, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Binotto
authors.affiliation: Department of Medicine, Division of Hematology, University of Padova, Padova, Italy.|Laboratory of Normal and Malignant Hematopoiesis, Venetian Institute of Molecular Medicine, Padova, Italy.
authors.forename: R
authors.initials: R
authors.lastname: Zambello
authors.affiliation: Department of Medicine, Division of Hematology, University of Padova, Padova, Italy.|Laboratory of Normal and Malignant Hematopoiesis, Venetian Institute of Molecular Medicine, Padova, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Semenzato
authors.affiliation: Department of Medicine, Division of Hematology, University of Padova, Padova, Italy.|Laboratory of Normal and Malignant Hematopoiesis, Venetian Institute of Molecular Medicine, Padova, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Gurrieri
authors.affiliation: Department of Medicine, Division of Hematology, University of Padova, Padova, Italy.|Laboratory of Normal and Malignant Hematopoiesis, Venetian Institute of Molecular Medicine, Padova, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Piazza
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000494:pharmacology; D015415:Biomarkers; D047390:Casein Kinase II / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D002453:Cell Cycle / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D005260:Female; D000071316:Forkhead Box Protein O3 / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression; D006801:Humans; D016130:Immunophenotyping; D015470:Leukemia, Myeloid, Acute / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D016328:NF-kappa B / Q000378:metabolism*; D014411:Neoplastic Stem Cells / Q000378:metabolism*; D063150:Polycomb Repressive Complex 1 / Q000235:genetics / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D000970:Antineoplastic Agents; D015415:Biomarkers; C499517:FOXO3 protein, human; D000071316:Forkhead Box Protein O3; D016328:NF-kappa B; D047428:Protein Kinase Inhibitors; D050796:STAT3 Transcription Factor; D000255:Adenosine Triphosphate; D063150:Polycomb Repressive Complex 1; D047390:Casein Kinase II; D051057:Proto-Oncogene Proteins c-akt