BMSEHA15
Published online 27 August 2009
Haematologica, Vol 95, Issue 1, 110-118 doi:10.3324/haematol.2009.010272
Copyright © 2010 by Ferrata Storti Foundation
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Chronic Lymphocytic Leukemia

Akt is activated in chronic lymphocytic leukemia cells and delivers a pro-survival signal: the therapeutic potential of Akt inhibition

Jianguo Zhuang1, Stephen F. Hawkins1, Mark A. Glenn1, Ke Lin2, Gillian G. Johnson2, Anthony Carter2, John C. Cawley1,2, Andrew R. Pettitt1,2

1 Division of Hematology, School of Cancer Studies, University of Liverpool, Liverpool
2 Department of Hematology, Royal Liverpool and Broadgreen University Hospitals NHS Trust, Liverpool, UK

Correspondence: Jianguo Zhuang, Division of Hematology, School of Cancer Studies, University of Liverpool,3rd Floor Duncan Building, Daulby Street, Liverpool, L69 3GA, UK. E-mail: j.zhuang{at}liv.ac.uk.

Background: The aims of the present study were to ascertain the activation status of Akt in the primary cells of chronic lymphocytic leukemia and to investigate the effects of specific Akt inhibition on chronic lymphocytic leukemia-cell survival.

Design and Methods: Anti-phospho-Akt (Ser473 or Thr308) antibodies and western blotting were used to establish the activation status of Akt. The effects of two different, specific small-molecule inhibitors (A-443654 or Akti-1/2) or small interfering RNA on cell survival and downstream targets of Akt were assessed. Apoptosis was determined by fluorescence-activated cell sorting analysis of phosphatidylserine exposure and by measurement of PARP cleavage. The phosphorylation status of GSK-3 and MDM2, two immediate downstream substrates of Akt, levels of the anti-apoptotic proteins BCL2 and MCL1, and expression of p53 and p21 were all measured by western blotting.

Results: Fully activated Akt was demonstrable in all chronic lymphocytic leukemia clones examined (n=26). These results were validated with extensive controls and it was shown that a harsh method of cell extraction is needed for detection of the active enzyme. Specific inhibition of Akt induced extensive apoptosis of chronic lymphocytic leukemia cells, which was associated with both a rapid loss of MCL1 through proteasomal degradation and increased expression of p53. Moreover, the Akt inhibitors, at concentrations that induced extensive apoptosis in chronic lymphocytic leukemia cells, had little or no effect on normal peripheral blood mononuclear cells.

Conclusions: Chronic lymphocytic leukemia clones consistently contain activated Akt which plays a pivotal role in maintaining cell survival. Inhibition of the Akt pathway may be of potential value as a novel therapeutic strategy in chronic lymphocytic leukemia.

Key words: Akt, Akt inhibitors, apoptosis, chronic lymphocytic leukemia, MCL1.


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