Sinclair, PB; (2002) A fluorescence in-situ hybridisation and molecular investigation of leukaemia associated abnormalities of chromosome 6q. Doctoral thesis , University of London.

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Abstract

Deletions of the long arm of chromosome 6 are a recognised recurrent cytogenetic abnormality associated with ALL. Balanced rearrangements of 6q are less common but occur in leukaemias of both lymphoid and myeloid origin. With the aim of identifying genes that contribute to leukaemia through loss or rearrangement the breakpoints of translocations and deletions of 6q were mapped by FISH. Comparison between the mapped deletions led to the identification of a 4.8 Mb CDR and candidate tumour suppressor gene (GluR-6). Expression of GluR-6 was demonstrated to occur in haernatologic tissues and mutation analysis was performed on leukaemic samples with clonal deletions of the region. In one of 14 cases a base pair substitution that led to a change in amino acid sequence was found. The base pair substitution was also present in the patients' remission sample but was not seen in any of 20 other normal bone marrow samples analysed. Analysis of the translocations identified a variety of breakpoints between 6q15 and 6q27, with none positioned within the CDR. In seven cases breakpoints clustered within a 14 Mb region of 6q22-q23 but different subregions were defined for five analysed in detail. Complex rearrangements in one case of ALL appeared to result in translocation of one homologue of 6q and deletion of the second. Detailed FISH analysis defined a translocation breakpoint falling between two PACs that contained exons of a known tumour suppressor gene, the IGF2-R. Southern blot analysis failed to confirm disruption of the IGF2-R, but an IGF2-R-Afl? P8 fusion transcript was cloned by RACE PCR from the patients' c-DNA. Involvement of MRP8 in the translocation remains in doubt because attempts to confirm the presence of the fusion transcript were unsuccessful.

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