Targeting CK2 overexpression and hyperactivation as a novel therapeutic tool in chronic lymphocytic leukemia.
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 coculture 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 increased 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, β2 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.
Martins
Leila R
LR
Cancer Biology Unit, Instituto de Medicina Molecular, Lisbon University Medical School, Lisbon, Portugal.
Lúcio
Paulo
P
Silva
Milene C
MC
Anderes
Kenna L
KL
Gameiro
Paula
P
Silva
Maria G
MG
Barata
João T
JT
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D001402:B-Lymphocytes / Q000187:drug effects; D016022:Case-Control Studies; D047390:Casein Kinase II / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D004789:Enzyme Activation; D005260:Female; D015870:Gene Expression; D006801:Humans; D066298:In Vitro Techniques; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D008297:Male; D008875:Middle Aged; D051059:PTEN Phosphohydrolase / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000235:genetics; D013601:T-Lymphocytes / Q000187:drug effects
D047428:Protein Kinase Inhibitors; D034741:RNA, Small Interfering; D047390:Casein Kinase II; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human