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

SIMPLE SUMMARY: Chronic lymphocytic leukaemia (CLL) is the most common blood cancer in the Western world and remains incurable. While a cause for this cancer has not been defined, one specific protein, protein kinase CβII (PKCβII), is highly expressed in CLL cells and is linked with a poorer clinical outcome. This study shows that PKCβ expression plays a central role in assisting the development of leukemic cells in our CLL mouse model. Moreover, a ubiquitously expressed protein SP1 is important for driving the genetic program that promotes leukaemia in our model system, and this program is assisted by PKCβ. Importantly, this SP1-driven program is also observed in human CLL cells, suggesting a role for PKCβ in the development of human disease. 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.