title: On CK2 regulation of chronic lymphocytic leukemia cell viability.
abstract: Specific inhibition of signaling elements essential for the viability of B-cell chronic lymphocytic leukemia (CLL) cells offers great promise for the design of more efficient therapies. The protein serine/threonine kinase CK2 is frequently upregulated in cancer, and it is overexpressed and hyperactivated in primary CLL cells from untreated patients. We have shown that inhibition of CK2 induces apoptosis of CLL cells, whereas it does not significantly impact normal lymphocytes, demonstrating the selectivity of the CK2 inhibitors toward leukemia cells. Notably, although co-culture with OP9 stromal cells and BCR stimulation both promote leukemia cell survival in vitro, they do not prevent apoptosis of CLL cells treated with CK2 inhibitors. PI3K signaling pathway was previously shown to be essential for CLL cell viability, an observation we confirmed in all patient samples analyzed. Further, we observed that CK2 blockade decreases PTEN phosphorylation, leading to PTEN activation, and that apoptosis of CLL cells upon CK2 inhibition is mediated by PKC inactivation. This suggests that activation of PI3K/PKC signaling pathway is involved in the pro-survival effects of CK2 in CLL cells. Sensitivity to CK2 inhibition does not correlate with expression of ZAP-70 or CD38, or with IGVH mutation status. However, it positively correlates with the percentage of CLL cells in the peripheral blood, β2 microglobulin levels, and Binet clinical stage. CK2 appears to play an important role in the biology of CLL and constitutes a promising target for the development of leukemia-specific therapies.
authors.affiliation: Cancer Biology Unit, Instituto de Medicina Molecular, Faculdade de Medicina da Universidade de Lisboa, Av. Prof. Egas Moniz, Lisbon 1649-028, Portugal.
authors.forename: Leila R
authors.initials: LR
authors.lastname: Martins
authors.forename: Paulo
authors.initials: P
authors.lastname: Lúcio
authors.forename: Milene C
authors.initials: MC
authors.lastname: Silva
authors.forename: Paula
authors.initials: P
authors.lastname: Gameiro
authors.forename: Maria G
authors.initials: MG
authors.lastname: Silva
authors.forename: João T
authors.initials: JT
authors.lastname: Barata
mesh_terms: D000818:Animals; D047390:Casein Kinase II / Q000037:antagonists & inhibitors / Q000378:metabolism*; D002469:Cell Separation; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D018920:Coculture Techniques; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000201:enzymology* / Q000473:pathology*; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000201:enzymology; D051379:Mice; D047428:Protein Kinase Inhibitors / Q000494:pharmacology
chemical_list: D047428:Protein Kinase Inhibitors; D047390:Casein Kinase II