cx-4945 and Leukemia--Myelogenous--Chronic--BCR-ABL-Positive

Chronic myeloid leukaemia (CML) is driven by the fusion protein Bcr-Abl, a constitutively active tyrosine kinase playing a crucial role in initiation and maintenance of CML phenotype. Despite the great efficacy of the Bcr-Abl-specific inhibitor imatinib, resistance to this drug is recognized as a major problem in CML treatment. We found that in LAMA84 cells, characterized by imatinib-resistance caused by BCR-ABL1 gene amplification, the pro-survival protein kinase CK2 is up-regulated as compared to the sensitive cells. CK2 exhibits a higher protein-level and a parallel enhancement of catalytic activity. Consistently, CK2-catalysed phosphorylation of Akt-Ser129 is increased. CK2 co-localizes with Bcr-Abl in the cytoplasmic fraction as judged by subcellular fractionation and fluorescence immunolocalization. CK2 and Bcr-Abl are members of the same multi-protein complex(es) in imatinib-resistant cells as demonstrated by co-immunoprecipitation and co-sedimentation in glycerol gradients. Cell treatment with CX-4945, a CK2 inhibitor currently in clinical trials, counteracts CK2/Bcr-Abl interaction and causes cell death by apoptosis. Interestingly, combination of CX-4945 with imatinib displays a synergistic effect in reducing cell viability. Consistently, knockdown of CK2α expression by siRNA restores the sensitivity of resistant LAMA84 cells to low imatinib concentrations. Remarkably, the CK2/Bcr-Abl interaction and the sensitization towards imatinib obtained by CK2-inhibition in LAMA84 is observable also in other imatinib-resistant CML cell lines. These results demonstrate that CK2 contributes to strengthen the imatinib-resistance phenotype of CML cells conferring survival advantage against imatinib. We suggest that CK2 inhibition might be a promising tool for combined strategies in CML therapy.

Topics: Antineoplastic Agents; Apoptosis; Benzamides; Casein Kinase II; Drug Resistance, Neoplasm; Fusion Proteins, bcr-abl; Gene Knockdown Techniques; Humans; Imatinib Mesylate; K562 Cells; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Naphthyridines; Phenazines; Piperazines; Proto-Oncogene Proteins c-akt; Pyrimidines; Signal Transduction