PKCβ Is Essential for the Development of CLL in the TCL1 Transgenic Mouse Model: Validation of PKCβ as a Therapeutic Target in CLL

The development and the propagation of chronic lymphocytic leukemia (CLL) has been linked to signalling via the B-cell receptor (BCR). Protein kinase C (PKC) beta is an essential signalling element of the BCR and was recently shown to be overexpressed in human CLL. We used the TCL1 transgenic mouse model to directly target PKC beta in the development of murine CLL. While loss of PKC beta in wild type mice leads to a complete loss of CD5+ B cells in these mice, the targeted disruption of the PKC beta gene in Tcl1 transgenic mice did not abrogate the accumulation of CD5 positive B cells in the pretumor phase in these mice. This suggests that the basic survival signal transmitted by PKC beta in B1 cells can be substituted by the augmented Akt signalling in the Tcl1 transgenic cells. Yet despite this, PKC beta deficient TCL1 transgenic mice did not develop a CLL disease, suggesting a role of PKC beta in the establishment of the malignant clone. In fact PKC beta is likely to be essential for transformation in limiting the BCR signal via a negative feedback loop, suggesting that BCR signalling strength is an important component of the transformation process. In order to provide support for the potential of PKC beta as a drug target in CLL we targeted PKC beta with the specific inhibitor Enzastaurin. This led to killing of human CLL samples in vitro and this was independent of risk factors in the samples analysed. We thus propose that PKC beta may be a relevant target for the treatment of CLL.