PhD defence S. (Sophie) Ottema

Acute Myeloid Leukemia (AML) is a cancer of the blood that primarily affects the myeloid line of white blood cells. AML is a heterogeneous disease with wide variation in treatment success and survival. Different risk groups can be distinguished on the basis of i.a. genetic abnormalities found in the leukemia cells. In the study presented in this thesis, we studied a group of AML patients who have various abnormalities of the long arm of chromosome 3 that lead to the overexpression of the gene EVI1 (located at 3q26). This oncogenic expression leads to a blockade in hematopoietic differentiation myeloid cells what results in AML. These patients are usually refractory to treatment and have poor survival rates. In order to eventually develop better treatment options, the mechanism that causes EVI1 overexpression has been studied. We showed that although the chromosomal rearrangements of the 3q26/EVI1 locus differ between these patients, the mechanism of transcriptional activation of EVI1 is highly similar. Many of the translocations, inversions, insertions or other (complex) chromosomal rearrangements led to the hijacking of a strong enhancer of another myeloid active gene by EVI1, resulting overexpression of EVI1. In our study we used CRISPR-Cas9 technology to generate AML cell models with chromosomal aberrations in the EVI1 locus. With these models we showed which regulatory sequences play an essential role in enhancer-promoter interaction and EVI1 activation. The similarities found within these EVI1 overexpressing patients could argue for an equal (new) AML treatment of these patients. The model systems we have developed in our research can be used to screen drugs for effectiveness in this group of patients.

The PhD defences do not take place publicly in the usual way in the Senate Hall at campus Woudestein or in the Professor Andries Querido Room at the Erasmus MC. The candidates will defend their dissertation either in a small group or online.