The Study of Retroviral Sequences in Human Leukaemia

Moore, Richard Arthur (2001). The Study of Retroviral Sequences in Human Leukaemia. PhD thesis The Open University.



Retroviruses have been closely associated with cancer and leukaemia since their first discovery in the beginning of the 20th century. Many retroviruses both endogenous and exogenous have a direct causal role in leukaemia in many animal species. However in humans the only retrovirus that has been shown to cause leukaemia to date is HTLV-I with ATL. ATL generally affects those people within HTLV-I endemic areas in particular Japan, sub-Saharan Africa and the Caribbean basin. ATL cases in Europeans and Caucasians in general are very rare. In this thesis the HTLV-I sequence was isolated from a Greek Caucasian patient with ATL. The virus was subtyped and shown to novel and of the Cosmopolitan type A, the most internationally found subtype, known as the transcontinental variant. This data highlights the potential for further spread of this pathogenic virus into Western Europe and illustrates that ethnicity is not a barrier to ATL. This thesis supports the expansion of a screening programme throughout Europe including the UK.

Around 10% of the human genome is composed of sequences resulting of retrotransposition. One of the main sources of this RT activity is Human Endogenous Retrovirus-like sequences (HERV). This thesis details the isolation and characterisation of two novel HERV sequences. Their phylogeny is also considered with one HERV clustering within the HERV-I family and the second clustering in the HERV-XA family. A low copy number was estimate for both elements. PAC-FISH revealed their chromosomal locations and the relevance of these regions is discussed. Expression of both elements was analysed by RT-PCR using primers directed toward putative ORFs. This analysis revealed an expressed portion of the XA related element, spanning 880bp, in PBMC. This expression was analysed in 10 leukaemia cases and was illustrated to be higher in some AML cases. This data illustrates that even highly disrupted HERV have some coding potential and supports a possible role in leukaemogenesis for HERV in general.

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