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Proteomic analysis of B-cell receptor signaling in chronic lymphocytic leukaemia reveals a possible role for kininogen

Welham, Kevin J.; Kashuba, Elena; Eagle, Gina L.; Bailey, James; Eagle, Gina; Evans, Paul; Welham, Kevin; Welham, Kevin J.; Allsup, David; Cawkwell, Lynn

Authors

Kevin J. Welham

Elena Kashuba

Gina L. Eagle

James Bailey

Gina Eagle

Paul Evans

Kevin Welham

Kevin J. Welham

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Dr David Allsup D.J.Allsup@hull.ac.uk
Senior Lecturer in Haematology and Honorary Consultant



Abstract

CLL is an incurable disease with variable prognosis. The hyper reactivity of the B-cell receptor (BCR) to unknown antigen ligation plays a pivotal role in CLL-cell survival. We aimed to investigate the BCR signalling pathway using proteomics to identify novel proteins which may have clinical relevance in this disease.Three CLL samples were selected based upon BCR responsiveness, demonstrated by upregulation of phospho-ERK following in vitro stimulation. The differential expression of proteins, upon artificial stimulation of the BCR, was examined in these samples using two-dimensional gel electrophoresis in combination with mass spectrometry. Proteins of interest were subsequently examined using immunoblotting. Proteomic analysis revealed that kininogen, a critical protein of kinin-kallikrein system, was upregulated in all 3 clinical samples upon BCR stimulation. There are 2 forms of kininogen: HMWK and LMWK. The upregulation of LMWK upon BCR stimulation was confirmed by immunoblotting in all 3 of these samples. In a pilot series of 52 unselected CLL samples, 71% demonstrated basal LMWK expression. There was a trend towards shorter median survival in LMWK positive cases (147. months versus 253. months for LMWK negative cases; p=. 0.125). Kininogen may be a novel therapeutic target in CLL and the possible association with prognosis warrants further investigation. Biological significance: We have identified the upregulation of LMWK upon BCR stimulation of CLL samples. There is no previous published research to suggest a link between kininogen and normal B-cells or CLL cells. In 52 unselected CLL samples, 71% demonstrated basal LMWK expression. There was a trend towards shorter median survival in LMWK positive cases. The absence of LMWK protein expression on normal B-cells suggests that this could be a biomarker for CLL and further research should be undertaken. © 2013 Elsevier B.V.

Journal Article Type Article
Publication Date Oct 8, 2013
Journal Journal of proteomics
Print ISSN 1874-3919
Electronic ISSN 1876-7737
Publisher Elsevier
Peer Reviewed Peer Reviewed
Volume 91
Pages 478-485
APA6 Citation Kashuba, E., Eagle, G. L., Bailey, J., Evans, P., Welham, K. J., Allsup, D., & Cawkwell, L. (2013). Proteomic analysis of B-cell receptor signaling in chronic lymphocytic leukaemia reveals a possible role for kininogen. Journal of Proteomics, 91, (478-485). doi:10.1016/j.jprot.2013.08.002. ISSN 1874-3919
DOI https://doi.org/10.1016/j.jprot.2013.08.002
Keywords Chronic lymphocytic leukaemia; B-cell receptor; Kininogen; Proteomics
Publisher URL http://www.sciencedirect.com/science/article/pii/S1874391913004405
Additional Information This article is maintained by: Elsevier; Article Title: Proteomic analysis of B-cell receptor signaling in chronic lymphocytic leukaemia reveals a possible role for kininogen; Journal Title: Journal of Proteomics; CrossRef DOI link to publisher maintained version: http://dx.doi.org/10.1016/j.jprot.2013.08.002; Content Type: article; Copyright: Copyright © 2013 Elsevier B.V. All rights reserved.