PKCβ Facilitates Leukemogenesis in Chronic Lymphocytic Leukaemia by Promoting Constitutive BCR-Mediated Signalling

B cell antigen receptor (BCR) signalling competence is critical for the pathogenesis of chronic lymphocytic leukaemia (CLL). Defining key proteins that facilitate these networks aid in the identification of targets for therapeutic exploitation. We previously demonstrated that reduced PKC alpha function in mouse hematopoietic stem/progenitor cells (HPSCs) resulted in PKC beta II upregulation and generation of a poor-prognostic CLL-like disease. Here, prkcb knockdown in HSPCs leads to reduced survival of PKC alpha-KR-expressing CLL-like cells, concurrent with reduced expression of the leukemic markers CD5 and CD23. SP1 promotes elevated expression of prkcb in PKC alpha-KR expressing cells enabling leukemogenesis. Global gene analysis revealed an upregulation of genes associated with B cell activation in PKC alpha-KR expressing cells, coincident with upregulation of PKC beta II: supported by activation of key signalling hubs proximal to the BCR and elevated proliferation. Ibrutinib (BTK inhibitor) or enzastaurin (PKC beta II inhibitor) treatment of PKC alpha-KR expressing cells and primary CLL cells showed similar patterns of Akt/mTOR pathway inhibition, supporting the role for PKC beta II in maintaining proliferative signals in our CLL mouse model. Ibrutinib or enzastaurin treatment also reduced PKC alpha-KR-CLL cell migration towards CXCL12. Overall, we demonstrate that PKC beta expression facilitates leukemogenesis and identify that BCR-mediated signalling is a key driver of CLL development in the PKC alpha-KR model.

Automated summary

The expression of PKC beta facilitates leukemogenesis in chronic lymphocytic leukemia (CLL) and BCR-mediated signaling is identified as a key driver of CLL development in the PKC alpha-KR model.