Cryptic Chromosome Abormalities in Acute Leukaemia: Identification and Detection
(Cryptische chromosomeafwijkingen in acute leukemie: identificatie en detectie)
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Specific chromosome aberrations are observed in 50% of all new acute leukaemia patients. As a result of chromosome aberrations, genes located at the breakpoints can be disrupted and fusion genes can be formed. In addition, genes can be lost or amplified. An increasing number of these rearrangements are specific and can be correlated with diagnosis, prognosis and response to therapy. In the other 50% of new leukaemia patients no or non-specific abnormalities are found. It is thought that also in this group specific chromosome abnormalities are present, but that these are cryptic and not detectable using conventional karyotyping. The aim of this thesis was to identify these cryptic chromosome aberrations. The different chapters demonstrate examples of the stages distinguishable in research concerning chromosome aberrations in acute leukaemia. In the first phase, we identified five new chromosome abnormalities, each present in a single case until now. More cases need to be identified before these aberrations can be labelled as recurrent and additional research should be performed to obtain more insight into the breakpoints, incidence and clinical relevance. Additionally, we identified frequently lost and gained chromosome regions, which may be narrowed down to single genes involved in leukaemogenesis. In the second phase, we developed diagnostic split-signal FISH assays for easy diagnostic detection of the t(5;14)(q35;q32). Using these probe sets, we identified five new cases involving HOX11L2 in our lab. For detection of NUP98 rearrangements we used split signal FISH as well, and we showed NUP98 aberrations are very rare, being present in 2/84 cases studied. As an example of ! the last phase in research, we showed that CDKN2 deletions do not constitute a prognostic factor in childhood c/preB-ALL.