PhD defence S. (Sanne) Noort

Dissertation in short:

In this thesis we have investigated novel driving aberrations in pediatric AML as in 30% of patients no apparent driving aberration can be detected. Ultimately we aim to improve risk group stratification and potentially identify novel targets for therapy to improve outcome. We did this using next generation sequencing such as whole exome-, whole genome-, and RNA-sequencing. Using these techniques we were able to identify driving aberrations and mutations in 65% of patients in whom no aberration was detected previously. We investigated various rare and not previously described aberrations. Some of these aberrations were associated with a poor outcome, such as rearrangements involving a gene called ERG and NUP98-KDM5A. Whereas others had a more favorable outcome such as RUNX1-CBFA2T3. Interestingly, we also found similarities between different types of cancer. For example, there is an overlap between T-cell acute lymfoblastic leukemia and AML. Furthermore the gene expression ERG-rearrangements, was similar gene expression of Ewing Sarcoma, a type of bone cancer. Furthermore, we investigated GATA1 mutations in neonates with Down syndrome using targeted deep sequencing, as children with Down syndrome are at higher risk of development of transient myeloid leukemia and subsequently myeloid leukemia. This proved to be a more sensitive technique to detect transient myeloid dysplasia, compared to determining blast percentage in peripheral blood of neonates with Down syndrome.  In conclusion we have shown that next-generation sequencing is an important tool to detect aberrations with an impact on outcome and should become standard of care in pediatric AML diagnostics.