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Leukaemia is a genetic disease.In many cases, recombination between the DNA
which encodes genes at different chromosomal sites in bone marrow progenitor
cells gives rise to functional fusion genes with leukaemia-causing properties.
Chromosome interchanges or "translocations" are the microscopically
visible products of this recombination. We seek to better understand the cause
of somatic gene recombination in myeloid leukaemia, using complex variants of
the BCR-ABL1 fusion gene rearrangement in chronic myeloid leukaemia (CML) as
our model.
We have completed DNA sequence analysis of all recombination sites (breakpoints)
of a complex BCR-ABL1 rearrangement found in the leukaemic cells of a CML patient.
Sequences were aligned and recurring motifs that might give clues to the
cause of the DNA recombination event identified. In this and two other cases,
coding regions of genes additional to BCR and ABL1 have been identified at sites
of chromosome breakage and rejoining that were previously considered incidental.
Structural and functional characteristics of these genes and others accessed at
recombination sites on other chromosomes from different patients will be determined
molecularly.
These studies will provide an overall indication of the frequency and kinds of
different genes involved in complex BCR-ABL1 rearrangements, and will allow access
to sequences at precise sites of breakage for further detailed analysis. The relevance
of additional gene involvement to the biology and pathology of the disease is also
being explored.
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