PKCβ facilitates leukemogenesis in chronic lymphocytic leukaemia by promoting constitutive BCR-mediated signalling

Hay, J. et al. (2022) PKCβ facilitates leukemogenesis in chronic lymphocytic leukaemia by promoting constitutive BCR-mediated signalling. Cancers, 14(23), 6006. (doi: 10.3390/cancers14236006) (PMID:36497487) (PMCID:PMC9735720)

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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.

Item Type:Articles
Glasgow Author(s) Enlighten ID:Hay, Dr Jodie and Tarafdar, Ms Anuradha and Dunn, Mrs Karen and Moka, Miss Hothri Ananyamb and Lees, Mr Jamie and Holroyd, Dr Ailsa and Malik, Miss Natasha and Michie, Professor Alison and Almuhanna, Hassan Nasser B and Cassels, Miss Jennifer
Authors: Hay, J., Tarafdar, A., Holroyd, A. K., Moka, H. A., Dunn, K. M., Alshayeb, A., Lloyd, B. H., Cassels, J., Malik, N., Khan, A. F., Sou, I., Lees, J., Almuhanna, H. N.B., Kalakonda, N., Slupsky, J. R., and Michie, A. M.
College/School:College of Medical Veterinary and Life Sciences > School of Cancer Sciences
Journal Name:Cancers
ISSN (Online):2072-6694
Published Online:06 December 2022
Copyright Holders:Copyright © 2022 The Authors
First Published:First published in Cancers 14(23): 6006
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
168056Regulation of PKC-beta gene expression in in CLL cells.Alison MichieBloodwise (BLOODWIS)13012CS - Paul O'Gorman Leukaemia Research Centre
163632Development of a flow cytometry service within the Paul O'Gorman Leukaemia Research CentreAlison MichieThe Kay Kendall Leukaemia Fund (KENDALL)KKL501CS - Paul O'Gorman Leukaemia Research Centre
169717Elucidating the role of mTor kinase signalling in chronic lymphocytic leukaemiaAilsa HolroydThe Kay Kendall Leukaemia Fund (KENDALL)KKL838CS - Paul O'Gorman Leukaemia Research Centre
303091Elucidating the mechanisms that regulate FOXO activity in chronic lymphocytic leukaemia - a novel target for therapeutic exploitation?Alison MichieBloodwise (BLOODWIS)18003CS - Paul O'Gorman Leukaemia Research Centre
190660MRC Doctoral Training Grant 2013/14 and 2014/15George BaillieMedical Research Council (MRC)MR/K501335/1MVLS - Graduate School