Translational Profiling of Chronic Lymphocytic Leukaemia
thesisposted on 26.05.2011, 10:21 by Helen Rogers
B cell chronic lymphocytic leukaemia (B-CLL) is the most common form of adult leukaemia in the western world, characterised by the slow accumulation of small mature B lymphocytes in the circulating blood. Disease progression is prolonged and patients may survive for more than 20 years, however it ultimately remains incurable with conventional chemotherapy. Regulation of gene expression is a complex process and exerted at multiple steps in the expression pathway, including translation. Translational regulation has not previously been studied in B-CLL yet may be important as there are numerous examples of translation de-regulation in tumorigenesis. Results obtained suggest that a reduced level of protein synthesis was occurring in B-CLL cells. Furthermore, cDNA microarray analysis was performed providing a gene expression profile at the level of translation, which correlates with the biology of the disease. Internal ribosome entry could be a possible mechanism of up-regulation utilised, and evidence is provided to suggest this may be the case. Potential IRES activity was observed for three genes, found to be translationally up-regulated in B-CLL cells by the cDNA microarray analysis, under normal and serum starvation conditions. The microarray data provides some potential new targets for treatment. In particular, the up-regulation of the angiotensin II type 1 receptor may influence survival of B-CLL cells. Initial evidence suggests that its ligand angiotensin II could influence B-CLL cell survival. Median survival of B-CLL patients is 10 years, however disease progression is variable; some patients will survive for many years while others have a more aggressive form and die within a couple of years. Progression has been observed to correlate with the mutational status of the immunoglobulin heavy chain variable (IgVH) genes. Differences in polysome association for the two subtypes were determined, using the microarray data obtained, identifying a number of genes that may be significant to the biology of the disease.