Wen-Hsin, S.L.; (2006) Lentiviral-based RNA interference of genes in leukaemic cells. Doctoral thesis , University of London.

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Abstract

Childhood leukemia is a common paediatric cancer in the developed world and the biologically diverse subtypes of this disease are characterised by specific chromosomal translocations that alter the normal proliferative and survival signals of haematopoietic cells. Despite of greatly improved cure rate of childhood leukaemias over the past years, younger patients with acute leukaemias involving E2A-HLF and MLL-ENL translocations still confer a poor prognosis that is associated with a very unfavourable outcome. The incidence of relapse after complete remission seems to crucially depend on a small population of leukaemic stem cells that survive from the initial therapy and sustain the disease. So far it has been unsuccessful to induce long-term gene silencing using siRNA technology in the primary haematopoietic cell lines and leukaemic stem cells. Thus, this project aimed to optimise the current 2nd generation of miR30-based shRNA lentiviral vector to achieve this. The silencing cassettes were delivered to the cells of interest by lentivirus and long-term expression was seen. The result revealed that effective E2A-HLF and MLL-ENL gene silencing was achieved while LM02 gene expression was not significantly knocked down by the predicted LM02 shRNA constructs. The most efficient lentiviral vectors against specific genes will then be used to infect leukaemic cells to test the effect on aspects of the leukaemic phenotype. Understanding of these fusion genes and identification of their downstream target genes in initiating and maintaining transformation events in the leukaemic stem cells may aid the development of revolutionary therapeutics that specifically target leukaemic stem cells. In conjunction with standard therapies, this approach could be more effective in treating MLL-ENL and E2A-HLF patients who tend to have an extremely unfavourable prognosis.

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