Kempski, Helena Maria; (1999) A molecular cytogenetic study of chromosome regions 11q23 and 21q22 in childhood leukaemia. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Non random chromosomal abnormalities are associated with specific subgroups of leukaemia. These abnormalities include structural rearrangements which frequently involve specific loci containing genes which have been implicated in leukaemogenesis. The object of this study, was to explore two specific chromosomal regions, 11q23 and 21q22, frequently associated with leukaemias seen in early childhood. Abnormalities of chromosome 11 at band q23 (which usually involve the MLL gene) are commonly found in infant leukaemias. Using fluorescence in situ hybridisation (FISH) with locus-specific probes spanning the region between D11S622 and THY1, which includes MLL, subtle inter- and intra-chromosomal changes were detected in the leukaemic cells from a series of infant patients showing complex or ambiguous rearrangements involving 11q23. These include duplication, insertion, rearrangement and loss of heterozygosity for MLL, and the involvement of loci immediately proximal and distal to the gene. Structural and numerical changes of chromosome 21 are common in childhood leukaemia and include several well characterised translocations involving the AML1 gene at 21q22. Using FISH with a panel of locus-specific probes for chromosome 21, acquired structural abnormalities have been characterised in patients with Down syndrome (DS) (trisomy 21) and leukaemia, and neonates with transient abnormal myelopoiesis (TAM) (both DS and non-DS). Subtle structural changes were detected in each group of patients, providing evidence for the instability of chromosome 21 in the form of cryptic intra-clonal changes such as deletions and translocations undetectable by conventional cytogenetics. This work, on chromosome 21, has resulted in two regions, one at 21q11.l, involving regions within and adjacent to locus D21S215, and one at 21q22.3, between the loci containing 7 and D21S55, now being actively investigated for the presence of novel genes involved in leukaemogenesis as part of a subsequent PhD study and as an ongoing 5-year post-doctoral project.

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