We think that constitutively activated PTKs may contribute to PI-3k activation, because the Syk inhibitor, R406, induced CLL apoptosis and decreased phosphorylation of Akt and its targets Gsk3β and FoxO3a. However, constitutive PI-3k activity in CLL cells may also result from the phosphorylation and inactivation of Pten phosphatase by casein kinase 2 (Ck2), which negatively modulates PI-3k signalling by degrading PIP3 to PIP2. Ck2 contributes to oncogenesis by blockade of apoptosis and elevated expression of CSNK2A1 transcripts correlates with poor prognosis in CLL.
In T cell leukaemias, Ck2 inactivates Pten via phosphorylation of its C-terminus, resulting in the hyperactivation of PI-3k signalling. Ck2 activity and Pten phosphorylation were strikingly elevated in CLL cells relative to normal mononuclear cells or lymphocytes. Inhibition of Ck2 resulted in decreased phosphorylation of the Pten C-terminus and of apoptotic death.
It is unclear whether the implied anti-apoptotic actions of PI-3k are mediated via activation of Akt. Constitutively phosphorylated (i.e. activated) Akt was not found in some studies of CLL cells, although its activation was dramatically increased, for example by ligation of cell-surface CD160 or of CXCR4. In contrast, phosphorylated Akt was detected in CLL extracts in other studies. These conflicting data may result from the different methodologies used. Barragan et al reported that spontaneously activated Akt was detectable in fresh but not cryopreserved CLL cells, whereas Zhuang et al suggested that harsh extraction procedures were required for the detection of active Akt. Akt may promote CLL cell survival by blocking the Gsk3β-mediated proteasomal degradation of Mcl-1 and inhibition of Akt activation by the highly selective inhibitor Akt –I-1/2 resulted in apoptosis that was preceded by a decline in Mcl-1.
Targeted expression of the TCL1A gene within B cells of transgenic mice results in a disease resembling aggressive CLL. High TCL1 expression by CLL cells is predictive of a poor outcome and overexpression may be the result of decreased levels of the microRNAs mir-29 and miR-181. TCL1 is a co-activator of Akt and growth stimulation following ligation of the BCR correlates with TCL1 levels and with the kinetics of recruitment of Akt to the receptor complex. The high expression of TCL1 may contribute to aggressive disease by facilitating Akt activation following BCR stimulation.