ZAP-70 Phosphorylation and other prognostic factors in adult B-chronic lymphocytic leukaemia patients

Maramba, Aaron

Abstract

Abstract
B chronic lymphocytic leukaemia (B-CLL) is a disease with an enormously heterogeneous prognosis. Due to lack of effective treatments and the heterogeneity in its course, B-CLL has remained largely incurable. In the last two decades a number of biological markers have been recognised as prognostic parameters to replace clinical staging, chief among them is ZAP-70 (a T-cell cytoplasmic tyrosine protein) albeit without a full understanding of the mechanism involved.

The aim of this thesis was to identify reliable prognostic factors that could be used in the management of B-CLL patients. Seventy-six B-CLL patients were studied over 30 months using a random stratified method of sampling, whereby adult B-CLL patients were recruited at different stages of the disease. Retrospective studies enabled some patients to be studied for up to 192 months. ZAP-70 expression was demonstrated in some B-CLL cells and was examined for possible phosphorylation following B-CLL cells stimulation, implying its involvement in cell signalling. Through the use of a novel method developed during the present study, B-CLL cells were stimulated via the SDF1-α-CD184 signalling pathway resulting in ZAP-70 phosphorylation. Its expression and phosphorylation was investigated alongside other prognostic factors and also correlated with B-CLL progression. More importantly, this study demonstrated that ZAP-70 positive cells are more responsive to signals derived from their surrounding environment, such as SDF-1α.

In conclusion ZAP-70, CD38, and CD23 expressions together with IgVH gene mutational status were confirmed as indicators of poor prognosis. Response to external stimuli by some B-CLL cells, resulting in ZAP-70 phosphorylation represents the most novel aspect of this thesis and demonstrates ZAP-70 involvement in B-CLL signalling. Additionally, raised NK: B-CLL and T: B-CLL cell ratios were identified as good modifiable variable predictors of time to treatment that could be used for monitoring and therapeutic purposes. Since B-CLL is an incurable disease, the identification of prognostic factors could help in deciding the best time for intervention in B-CLL patients.

• Thesis Type: Thesis
• Deposit Date: May 30, 2013
• Publicly Available Date: May 19, 2016
• Keywords: leukaemia, cancer
• Public URL: https://uwe-repository.worktribe.com/output/931681
• Contract Date: May 19, 2016
• Award Date: May 29, 2013