B-cell receptor signaling in chronic lymphocytic leukemia cells is regulated by overexpressed active protein kinase CβII

Signals through the B-cell antigen receptor (BCR) are important for the survival of chronic lymphocytic leukemia (CLL) cells. Therefore, factors that influence these signals have important pathophysiological roles in this disease. One key mediator of BCR signaling is protein kinase C beta (PKC beta), which regulates the activation of I-kappa B kinases and the deactivation of Bruton tyrosine kinase within the signaling pathways initiated by BCR engagement. The present study demonstrates that overexpression of the PKC beta II isoform is a feature of CLL cells and that activity of this enzyme strongly correlates with CLL cell response to BCR engagement. Thus, intracellular Ca2+ release and increases in cell survival after BCR cross-linking were significantly greater in CLL patients with low levels than in CLL patients with high levels of active PKC beta II. Furthermore, BCR-Induced Ca2+ fluxes could be restored in CLL patients with high levels of active PKC beta II by pretreating the cells with the PKC beta-specific inhibitor LY3791196. Conversely, BCR-mediated intracellular Ca2+ release could be inhibited in CLL cells with low levels of active PKC beta II by pretreatment with the PKC agonist bryostatin. Taken together, these results demonstrate that overexpressed active PKC beta II plays a role in the regulation and outcome of BCR signals that can be important for the progression of CLL.