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

Abstract

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 PKCα function in mouse hematopoietic stem/progenitor cells (HPSCs) resulted in PKCβII upregulation and generation of a poor-prognostic CLL-like disease. Here, prkcb knockdown in HSPCs leads to reduced survival of PKCα-KR-expressing CLL-like cells, concurrent with reduced expression of the leukemic markers CD5 and CD23. SP1 promotes elevated expression of prkcb in PKCα-KR expressing cells enabling leukemogenesis. Global gene analysis revealed an upregulation of genes associated with B cell activation in PKCα-KR expressing cells, coincident with upregulation of PKCβII: supported by activation of key signalling hubs proximal to the BCR and elevated proliferation. Ibrutinib (BTK inhibitor) or enzastaurin (PKCβII inhibitor) treatment of PKCα-KR expressing cells and primary CLL cells showed similar patterns of Akt/mTOR pathway inhibition, supporting the role for PKCβII in maintaining proliferative signals in our CLL mouse model. Ibrutinib or enzastaurin treatment also reduced PKCα-KR-CLL cell migration towards CXCL12. Overall, we demonstrate that PKCβ expression facilitates leukemogenesis and identify that BCR-mediated signalling is a key driver of CLL development in the PKCα-KR model.

mTORC1-selective activation of translation elongation promotes disease progression in chronic lymphocytic leukemia

“…PKCα-KR CLL-like cells were responsive to IB treatment, as indicated by decreased Cyclin A expression, while proliferating human CLL cells did not illicit protein expression/synthesis responses to IB. Primary CLL cell proliferation was driven by CD40L/IL21 stimulation in this study, which occurs independently of BTK, while the PKCα-KR CLL mouse model exhibits activated BCR signalling with sensitivity to IB [ 17 , 44 ]. In addition, while PKCα-KR CLL exhibits increased RAP sensitivity, in terms of reducing tumour load in vivo, all CLL models displayed similar functional responses to AZD8055 and RAP.…”