PhD defence P.A. (Patricia) Olofsen-Dieleman

Severe congenital neutropenia (SCN) is a bone marrow failure syndrome characterized by a neutrophil differentiation block at the promyelocyte stage. SCN patients are effectively treated by colony stimulating factor 3 (CSF3/G-CSF) administration, alleviating the neutropenia in >90% of patients. A major concern in treating SCN patients with CSF3 is the highly increased risk of developing myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML). Progression to MDS/AML is associated with the appearance of hematopoietic clones with somatic mutations in the gene encoding the CSF3 receptor (CSF3R), resulting in a truncated form of CSF3R with defective internalization and aberrant signaling properties.1-3 These clones can persist for months or years before MDS/AML, most frequently characterized by additional mutations in RUNX1, becomes clinically overt.1,4 The work presented in this thesis focusses on the mechanisms involved in the leukemic progression of SCN by modelling the various sequential steps in induced pluripotent stem cells (iPSC) or mice.

Due to corona, the PhD defences do not take place publicly in the usual way in the Senate Hall or in the Professor Andries Querido Room. The candidates will defend their dissertation either in a small group or online.