The role of the Kinin-Kallikrein System in chronic lymphocytic leukaemia

Kashuba, Elena

April 2014

Thesis or dissertation

© 2014 Elena Kashuba. All rights reserved. No part of this publication may be reproduced without the written permission of the copyright holder.

Chronic lymphocytic leukaemia (CLL) is an incurable heterogeneous disease. The identification of reliable and cost effective biomarkers is therefore imperative. A comparative proteomic approach was previously employed to study protein expression changes associated with in vitro BCR ligation. Kininogen, a critical protein of Kinin-Kallikrein System (KKS) was found to be upregulated (p≥2) in 3/3 “high risk” clinical samples upon BCR stimulation. Both High and Low Molecular Weight Kininogens (HMWK and LMWK, respectively) serve as a substrate from which Plasma and Tissue Kallikreins liberate Kinins, which in turn act upon B1 and B2 kinin receptors. This project aimed to investigate the role of the KKS in CLL and to identify novel proteins which may have clinical relevance in this disease.

Materials and Methods:
KKS was investigated using CLL clinical samples and a range of methods such as immunoblotting, reverse transcription polymerase chain reaction (RT-PCR), enzyme-linked immunosorbent assay (ELISA) and flow cytometry as appropriate.

The up regulation of LMWK upon in vitro BCR stimulation was confirmed by immunoblotting in 3/3 CLL samples previously used in a discovery phase proteomics. In a pilot series of 52 unselected CLL samples, 71% demonstrated basal LMWK expression. A total of 18 of these samples were also analysed for LMWK transcript, which was not detected in any of these samples. The expression of Kallikrein 6 was confirmed in 25 CLL samples. The B1 and B2 receptors were identified in 15 and 3 CLL samples, respectively. An elevated Bradykinin level was demonstrated in 27/36 (75%) plasma samples from CLL patients and was found to be associated with untreated (p=0.039) stage A (p=0.03) CLL and increased Plasma Kallikrein (p=0.001).

It has been demonstrated for the first time that CLL cells express the components for KKS signalling pathway, which can be further investigated for clinical relevance.

Hull York Medical School, The University of Hull and the University of York
Cawkwell, Lynn; Allsup, David
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