Skip to main content
SpringerLink
Log in

On CK2 regulation of chronic lymphocytic leukemia cell viability

  • Published:
Molecular and Cellular Biochemistry Aims and scope Submit manuscript

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Zenz T, Mertens D, Kuppers R, Dohner H, Stilgenbauer S (2010) From pathogenesis to treatment of chronic lymphocytic leukaemia. Nat Rev Cancer 10:37–50. doi:10.1038/nrc2764

    Google Scholar 

  2. Gribben JG, O’Brien S (2011) Update on therapy of chronic lymphocytic leukemia. J Clin Oncol 29:544–550. doi:10.1200/JCO.2010.32.3865

    Google Scholar 

  3. Barata JT (2011) The impact of PTEN regulation by CK2 on PI3K-dependent signaling and leukemia cell survival. Adv Enzyme Regul 51:37–49. doi:10.1016/j.advenzreg.2010.09.012

  4. Silva A, Yunes JA, Cardoso BA, Martins LR, Jotta PY, Abecasis M, Nowill AE, Leslie NR, Cardoso AA, Barata JT (2008) PTEN posttranslational inactivation and hyperactivation of the PI3K/Akt pathway sustain primary T cell leukemia viability. J Clin Investig 118:3762–3774. doi:10.1172/JCI34616

    Article  PubMed  CAS  Google Scholar 

  5. Silva A, Jotta PY, Silveira AB, Ribeiro D, Brandalise SR, Yunes JA, Barata JT (2010) Regulation of PTEN by CK2 and Notch1 in primary T-cell acute lymphoblastic leukemia: rationale for combined use of CK2- and gamma-secretase inhibitors. Haematologica 95:674–678. doi:10.3324/haematol.2009.011999

    Article  PubMed  CAS  Google Scholar 

  6. Kim JS, Eom JI, Cheong JW, Choi AJ, Lee JK, Yang WI, Min YH (2007) Protein kinase CK2alpha as an unfavorable prognostic marker and novel therapeutic target in acute myeloid leukemia. Clin Cancer Res 13:1019–1028. doi:10.1158/1078-0432.CCR-06-1602

    Google Scholar 

  7. Ringshausen I, Schneller F, Bogner C, Hipp S, Duyster J, Peschel C, Decker T (2002) Constitutively activated phosphatidylinositol-3 kinase (PI-3K) is involved in the defect of apoptosis in B-CLL: association with protein kinase Cdelta. Blood 100:3741–3748. doi:10.1182/blood-2002-02-0539

    Article  PubMed  CAS  Google Scholar 

  8. Martins LR, Lucio P, Silva MC, Anderes KL, Gameiro P, Silva MG, Barata JT (2010) Targeting CK2 overexpression and hyperactivation as a novel therapeutic tool in chronic lymphocytic leukemia. Blood 116:2724–2731. doi:10.1182/blood-2010-04-277947

    Article  PubMed  CAS  Google Scholar 

  9. Deglesne PA, Chevallier N, Letestu R, Baran-Marszak F, Beitar T, Salanoubat C, Sanhes L, Nataf J, Roger C, Varin-Blank N, Ajchenbaum-Cymbalista F (2006) Survival response to B-cell receptor ligation is restricted to progressive chronic lymphocytic leukemia cells irrespective of Zap70 expression. Cancer Res 66:7158–7166. doi:10.1158/0008-5472.CAN-06-0085

    Google Scholar 

  10. Shehata M, Schnabl S, Demirtas D, Hilgarth M, Hubmann R, Ponath E, Badrnya S, Lehner C, Hoelbl A, Duechler M, Gaiger A, Zielinski C, Schwarzmeier JD, Jaeger U (2010) Reconstitution of PTEN activity by CK2 inhibitors and interference with the PI3-K/Akt cascade counteract the antiapoptotic effect of human stromal cells in chronic lymphocytic leukemia. Blood 116:2513–2521. doi:10.1182/blood-2009-10-248054

    Article  PubMed  CAS  Google Scholar 

  11. Slaton JW, Unger GM, Sloper DT, Davis AT, Ahmed K (2004) Induction of apoptosis by antisense CK2 in human prostate cancer xenograft model. Mol Cancer Res 2:712–721

    PubMed  CAS  Google Scholar 

  12. Herishanu Y, Perez-Galan P, Liu D, Biancotto A, Pittaluga S, Vire B, Gibellini F, Njuguna N, Lee E, Stennett L, Raghavachari N, Liu P, McCoy JP, Raffeld M, Stetler-Stevenson M, Yuan C, Sherry R, Arthur DC, Maric I, White T, Marti GE, Munson P, Wilson WH, Wiestner A (2011) The lymph node microenvironment promotes B-cell receptor signaling, NF-kappaB activation, and tumor proliferation in chronic lymphocytic leukemia. Blood 117:563–574. doi:10.1182/blood-2010-05-284984

    Article  PubMed  CAS  Google Scholar 

  13. Ghia P, Chiorazzi N, Stamatopoulos K (2008) Microenvironmental influences in chronic lymphocytic leukaemia: the role of antigen stimulation. J Intern Med 264:549–562. doi:10.1111/j.1365-2796.2008.02030.x

    Google Scholar 

  14. Quiroga MP, Balakrishnan K, Kurtova AV, Sivina M, Keating MJ, Wierda WG, Gandhi V, Burger JA (2009) B-cell antigen receptor signaling enhances chronic lymphocytic leukemia cell migration and survival: specific targeting with a novel spleen tyrosine kinase inhibitor, R406. Blood 114:1029–1037. doi:10.1182/blood-2009-03-212837

    Article  PubMed  CAS  Google Scholar 

  15. Seiffert M, Stilgenbauer S, Dohner H, Lichter P (2007) Efficient nucleofection of primary human B cells and B-CLL cells induces apoptosis, which depends on the microenvironment and on the structure of transfected nucleic acids. Leukemia 21:1977–1983. doi:10.1038/sj.leu.2404863

    Google Scholar 

  16. Petlickovski A, Laurenti L, Li X, Marietti S, Chiusolo P, Sica S, Leone G, Efremov DG (2005) Sustained signaling through the B-cell receptor induces Mcl-1 and promotes survival of chronic lymphocytic leukemia B cells. Blood 105:4820–4827. doi:10.1182/blood-2004-07-2669

    Article  PubMed  CAS  Google Scholar 

  17. Cuni S, Perez-Aciego P, Perez-Chacon G, Vargas JA, Sanchez A, Martin-Saavedra FM, Ballester S, Garcia-Marco J, Jorda J, Durantez A (2004) A sustained activation of PI3K/NF-kappaB pathway is critical for the survival of chronic lymphocytic leukemia B cells. Leukemia 18:1391–1400. doi:10.1038/sj.leu.2403398

    Google Scholar 

  18. Plate JM (2004) PI3-kinase regulates survival of chronic lymphocytic leukemia B-cells by preventing caspase 8 activation. Leuk Lymphoma 45:1519–1529. doi:10.1080/10428190410001683642

    Article  PubMed  CAS  Google Scholar 

  19. Weinberg JB, Volkheimer AD, Chen Y, Beasley BE, Jiang N, Lanasa MC, Friedman D, Vaccaro G, Rehder CW, Decastro CM, Rizzieri DA, Diehl LF, Gockerman JP, Moore JO, Goodman BK, Levesque MC (2007) Clinical and molecular predictors of disease severity and survival in chronic lymphocytic leukemia. Am J Hematol 82:1063–1070. doi:10.1002/ajh.20987

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

We are grateful to all the patients that made this study possible. This study was supported by the grant PIC/IC/83193/2007 from Fundação para a Ciência e a Tecnologia. LRM has an FCT-SFRH PhD fellowship.

Author information

Authors and Affiliations

  1. Cancer Biology Unit, Instituto de Medicina Molecular, Faculdade de Medicina da Universidade de Lisboa, Av. Prof. Egas Moniz, Lisbon, 1649-028, Portugal

    Leila R. Martins, Milene C. Silva & João T. Barata

  2. Faculdade de Ciências Médicas (FCM), Centro de Estudos de Doenças Crónicas (CEDOC), Universidade Nova de Lisboa and Instituto Português de Oncologia, Lisbon, Portugal

    Paulo Lúcio, Paula Gameiro & Maria G. Silva

Authors
  1. Leila R. Martins
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Paulo Lúcio
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Milene C. Silva
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Paula Gameiro
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Maria G. Silva
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. João T. Barata
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to João T. Barata.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Martins, L.R., Lúcio, P., Silva, M.C. et al. On CK2 regulation of chronic lymphocytic leukemia cell viability. Mol Cell Biochem 356, 51–55 (2011). https://doi.org/10.1007/s11010-011-0947-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11010-011-0947-6

Keywords

Search

Navigation