Peptide Inhibition of NF-kappa B subunits in Chronic Lymphocytic Leukaemia
Cardiff Metropolitan University
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Chronic Lymphocytic Leukaemia is a chronic malignant B-cell disorder characterised by the abnormal clonal proliferation and accumulation of neoplastic B-lymphocytes in the peripheral blood, bone marrow, lymph nodes and spleen. It is the most common leukaemia in the UK and the incidence of CLL markedly increases in those over the age of 65. Over many decades there has been a lot of research into new prognostic indicators and numerous treatment strategies however this is still an incurable disease. This project proposes to look at the effects of peptide inhibition of Nuclear Factor Kappa B (NF-κB) subunits in CLL. NF-κB is a nuclear protein; it is a factor of the nucleus of B-cells that binds to the enhancer of the kappa light chain of immunoglobulin. It is required for proper immune function however inappropriate activation can mediate inflammation and tumourigenesis. It has been shown that NF-κB activity is heterogeneous among CLL patients. The main NF-κB subunits in CLL are p50, p65 and c-Rel. Given NF-κB is important in the pathology of CLL, it represents an attractive target for therapeutic development. In this study we aimed to use specific peptides against p50 and p65 subunits that cross the cell membrane and block nuclear localisation. Separate malignant B-cell samples from CLL samples were incubated in the presence and absence of a range of concentrations of the NF-κB inhibitory peptides. Apoptosis was measured by Annexin V / Propidium Iodide labelling. The NF-κB p50 inhibitory peptide saw a greater than 60% of apoptotic activity, which was significantly different (p<0.0001) from that seen with the p65 inhibitory peptide. In a parallel experiment, mRNA was extracted from cells exposed to the inhibitory peptide and specific transcription of NF-κB regulated genes with QRT-PCR. We determined that both subunits are critical for the survival and proliferation of CLL cells and we also observed that all of the genes we looked at showed a significant degree of apoptosis with both the p50 and p64 inhibitory peptides, and it is believed that they pose an interesting potential for future therapeutic drugs for the treatment of CLL, although further work is being carried out by the Cardiff CLL Research Group to understand the full potential of these possible drugs.
MSc Biomedical Science
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