Generation of a poor prognostic chronic lymphocytic leukemia-like disease model: PKC subversion induces up-regulation of PKC II expression in B lymphocytes

Nakagawa, R. et al. (2015) Generation of a poor prognostic chronic lymphocytic leukemia-like disease model: PKC subversion induces up-regulation of PKC II expression in B lymphocytes. Haematologica, 100(4), pp. 499-510. (doi:10.3324/haematol.2014.112276) (PMID:25616575) (PMCID:PMC4380723)

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Abstract

Overwhelming evidence identifies the microenvironment as a critical factor in the development and progression of chronic lymphocytic leukemia, underlining the importance of developing suitable translational models to study the pathogenesis of the disease. We previously established that stable expression of kinase dead protein kinase C alpha in hematopoietic progenitor cells resulted in the development of a chronic lymphocytic leukemia-like disease in mice. Here we demonstrate that this chronic lymphocytic leukemia model resembles the more aggressive subset of chronic lymphocytic leukemia, expressing predominantly unmutated immunoglobulin heavy chain genes, with upregulated tyrosine kinase ZAP-70 expression and elevated ERK-MAPK-mTor signaling, resulting in enhanced proliferation and increased tumor load in lymphoid organs. Reduced function of PKCα leads to an up-regulation of PKCβII expression, which is also associated with a poor prognostic subset of human chronic lymphocytic leukemia samples. Treatment of chronic lymphocytic leukemia-like cells with the selective PKCβ inhibitor enzastaurin caused cell cycle arrest and apoptosis both in vitro and in vivo, and a reduction in the leukemic burden in vivo. These results demonstrate the importance of PKCβII in chronic lymphocytic leukemia-like disease progression and suggest a role for PKCα subversion in creating permissive conditions for leukemogenesis.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Michie, Dr Alison and Mccaig, Dr Alison and Dunn, Mrs Karen and Cosimo, Dr Emilio and Holroyd, Dr Ailsa and Tarafdar, Ms Anuradha and Nakagawa, Dr Rinako
Authors: Nakagawa, R., Vukovic, M., Tarafdar, A., Cosimo, E., Dunn, K., Mccaig, A. M., Holroyd, A., McClanahan, F., Ramsay, A. G., Gribben, J. G., and Michie, A.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
Journal Name:Haematologica
Publisher:Fondazione Ferrata Storti
ISSN:0390-6078
ISSN (Online):1592-8721
Copyright Holders:Copyright © 2015 The Authors
First Published:First published in Haematologica 100(4):499-510
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
444831Defining the cellular origin of chronic lymphocytic leukaemiaAlison MichieMedical Research Council (MRC)G0601099RI CANCER SCIENCES
600561MICA: Determining the therapeutic potential of targeting mTORC-1/2 in chronic lymphocytic leukaemia - a pre-clinical studyAlison MichieMedical Research Council (MRC)MR/K014854/1ICS - PAUL O'GORMAN LEUKAEMIA RESEARCH C
591941Regulation of PKC-beta gene expression in in CLL cells.Alison MichieLeukaemia & Lymphoma Research (LRF)13012ICS - PAUL O'GORMAN LEUKAEMIA RESEARCH C
542691Development of a flow cytometry service within the Paul O'Gorman Leukaemia Research CentreAlison MichieThe Kay Kendall Leukaemia Fund (KENDALL)KKL501RI CANCER SCIENCES