Stranks, Gail; (1996) Abnormalities of chromosome 9p in lymphoid malignancies. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

The aim of this thesis was to determine the genes involved in the recurrent chromosome 9p abnormalities seen in lymphoid malignancies. In particular, the frequency and extent of deletions involving the p16INK4A tumour suppressor gene at 9p21 in haematologic tumours was investigated. The involvement of MYC at 8q24 with candidate genes at 9p13.3 in the translocation t(8;9)(q24.1 ;p13.3) was also studied. Deletion of the cyclin dependant kinase inhibitor p16INK4A had been implicated in leukaemogenesis by limited studies on cell lines. Analysis here of 231 primary tumours showed that biallelic deletions of p16INK4A occurred in 18% of B-cell precursor acute lymphoblastic leukaemia (BCP-ALL) and in some high grade and transformed non-Hodgkin's lymphomas (NHL). Abnormalities of p16INK4A were shown to correlate with the ability of BCP-ALL to grow in SCID mice. Deletions of p16INK4A were frequently undetectable cytogenetically, and their extent was variable, although most also involved the closely linked gene p15INK4B which may also function as a tumour suppressor gene. Analysis of heterozygosity indicated that a third lymphoid tumour suppressor gene may exist centromeric to p15INK4B on chromosome 9p. The recurrent translocation t(8;9)(q24.1;p13.3) has been reported in high grade B-cell NHL and mature B-cell leukaemias. Two cell lines which possessed this translocation showed overexpression of MYC mRNA. Pulsed field electrophoresis showed that in one cell line the breakpoint was within 70 kb 3' of the MYC gene, but this could not be pinpointed by conventional electrophoresis with the available probes for the region 3' of MYC nor with probes for candidate genes from 9p21. Finally, allelic restriction of the expression of MYC was investigated in a B-NHL cell line showing duplication of one MYC allele and translocation of the other. Sequence analysis of PCR amplified genomic DNA and mRNA showed that only the translocated allele was transcribed.

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