Targeting CK2 overexpression and hyperactivation as a novel therapeutic tool in chronic lymphocytic leukemia

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BlankBlood First Edition Paper, prepublished online July 21, 2010; DOI

10.1182/blood-2010-04-277947.

Targeting CK2 overexpression and hyperactivation as a novel therapeutic tool in

chronic lymphocytic leukemia

Leila R. s1, o Lúcio2, Milene C. Silva1, Kenna L. Anderes3, a

Gameiro2, G. Silva2 and João T. Barata1,*

1 Cancer Biology Unit, Instituto de Medicina Molecular, Lisbon University

Medical School, Lisbon, Portugal; 2 CEDOC, Faculdade de Ciencias Medicas, FCM,

Universidade Nova de Lisboa and Instituto Portugues de Oncologia, Lisbon,

Portugal; 3 Cylene Pharmaceuticals, San Diego, CA, United States

* Corresponding author; email: joao_barata@...

Abstract

Expression of protein kinase CK2 is frequently deregulated in cancer and

mounting evidence implicates CK2 in tumorigenesis. Here, we show that CK2 is

overexpressed and hyperactivated in chronic lymphocytic leukemia (CLL).

Inhibition of CK2 induces apoptosis of CLL cells without significantly affecting

normal B and T lymphocytes. Importantly, this effect is not reversed by

co-culture with OP9 stromal cells, which are otherwise capable of rescuing CLL

cells from in vitro spontaneous apoptosis. CLL cell death upon CK2 inhibition is

mediated by inactivation of PKC, a PI3K downstream target, and correlates with

decreased PTEN activity, indicating that CK2 promotes CLL cell survival at least

in part via PI3K-dependent signaling. Although CK2 antagonists induce

significant apoptosis of CLL cells in all patient samples analyzed, sensitivity

to CK2 blockade positively correlates with the percentage of CLL cells in the

peripheral blood, ß2 microglobulin serum levels and clinical stage. These data

suggest that subsets of patients with aggressive and advanced stage disease may

especially benefit from therapeutic strategies targeting CK2 function. Overall,

our study indicates that CK2 plays a critical role in CLL cell survival, laying

the groundwork for the inclusion of CK2 inhibitors into future therapeutic

strategies.