Nasipuri, Soma; (1991) A molecular analysis of chromosome 11 band q23 in haematopoietic malignancy. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Rearrangements of chromosome 11 at band q23 have been observed in haematopoietic malignancies. These rearrangements are mainly translocations and involve other chromosomes, the most common being t(4;11)(q21;q23), t(9;11)(p22;q23) and t(11;19)(q23;p13). The molecular basis of these translocations is as yet unknown. The aim of this thesis is to characterise the 11q23 region at the molecular level and to study leukaemic patients with 11q23 involvement. Three main approaches have been used, namely mapping, rearrangement studies and isolation of novel probes. Mapping of various genes localised to 11q23 in relation to the leukaemic translocation breakpoints have been carried out using somatic cell hybrids. By studying different translocation breakpoints, relative positions of the breakpoints and genes in this region were determined. A novel method of gene mapping by the enzymatic amplification of flow-sorted chromosomes is described. This was used to map the c-ets-1, Thy-1 and CD3 genes distal to the breakpoint of the constitutional t(11;22)(q23;q11) translocation. Long range rearrangement studies of the Hq23 region by pulsed field gel electrophoresis are also described. Emphasis was on the c-ets-1, Thy-1 and CD3 genes. CD3G, a member of the CD3 gene complex, was found to be rearranged in the t(4;11) translocation and positioned within 200kb of the translocation breakpoint. In an attempt to clone the t(4;11) translocation breakpoint, yeast artificial chromosome clones positive for CD3 were isolated. They did not encompass the breakpoint and were localized approximately 100kb proximal to it. End-cloning of one of the clones were performed in order to isolate an overlapping telomeric yeast artificial chromosome clone. The pulsed field gel and yeast artificial chromosome studies lead to a more precise localisation of the t(4;11) translocation breakpoint. A novel technique of Alu-PCR was investigated and used on flow-sorted chromosomes for the generation of probes specific for the Hq23-q24 region. Eight novel probes to this region were generated and mapped in relation to the t(4;11) and the Ewing's sarcoma t(11;22) translocation breakpoints. The studies described have contributed to the knowledge of the molecular organization of the 11q23 region. This is important for the understanding of the molecular basis of 11q23 abnormalities, and their association with haematopoietic malignancy.

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