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Modelling the t(7;12) Infant Leukaemia using Gene Editing Technology

PhD projects for research students

The impact of chromosomal rearrangements on the genome organisation of leukaemia cells.

Chromosomal rearrangements are a hallmark of leukaemia. It is well known that specific chromosomal rearrangements are associated with certain leukaemia subtypes and that can predict clinical outcome. What is not well understood, is how these chromosomal rearrangements influence the genome organisation within the nuclear architecture of leukaemia cells.  The study of genome organisation is an emerging field of research in pathologies such as cancer. It has been shown that gene repositioning in the nuclei of cancer cells may be associated with abnormal gene expression. We and others have previously shown that gene repositioning may be due to chromosomal rearrangements affecting a particular locus. What exactly dictates the gene repositioning is matter of investigation. 
Useful background reading:
1. Bourne et al. (2013) Interphase Chromosome Behaviour in Normal and Diseased Cells, In: Yurov Y, Vorsanova SG, Iourov IY, editors. Human Interphase Chromosomes: the Biomedical Aspects, Springer, p. 9-33.
2. Ballabio et al. (2009) Ectopic expression of the HLXB9 gene is associated with an altered nuclear position in t(7;12) leukaemias. Leukemia 23:1179-1182
3. Roukos and Misteli (2014) The biogenesis of chromosome translocations. Nat Cell Biol 16:293-300.

This project aims at clarifying the contribution of chromosomal rearrangements to the genome organisation of leukaemic cells and at exploring the effects that gene repositioning might have on gene expression. As part of this project, leukaemia derived cell lines will be selected on the basis of specific chromosomal rearrangements. Fluorescence in situ hybridisation will be applied to those cell lines in order to map chromosomal breakpoints accurately and to identify specific loci of interest. Specific genes will be investigated for their expression levels using Quantitative Real Time PCR and for their radial nuclear positioning using specialised software.