On CK2 regulation of chronic lymphocytic leukemia cell viability.

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BlankOn CK2 regulation of chronic lymphocytic leukemia cell viability.

LR s, P Lucio, MC Silva, P Gameiro, MG Silva, and JT Barata

Mol Cell Biochem, July 13, 2011;

Cancer Biology Unit, Instituto de Medicina Molecular, Faculdade de Medicina da

Universidade de Lisboa, Av. Prof. Egas Moniz, Lisbon, 1649-028, Portugal.

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,

?2 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.

PMID: 21750986 .