PhD ceremony Ms. C.M. Woolthuis: The biology of human hematopoietic stem and progenitor cells in acute myeloid leukemia, aging and autologous transplantation

PhD ceremony: Ms. C.M. Woolthuis, 16.15 uur, Academiegebouw, Broerstraat 5, Groningen

Dissertation: The biology of human hematopoietic stem and progenitor cells in acute myeloid leukemia, aging and autologous transplantation

Promotor(s): prof. E. Vellenga, prof. J.J. Schuringa

Faculty: Medical Sciences

The hematopoietic system is capable of replenishing all mature blood cells during the complete lifespan of an individual. Hematopoietic stem cells are on top of the hierarchy, followed by specialised progenitors that ultimately differentiate into mature blood cells. In this thesis the biology of human hematopoietic stem and progenitor cells was studied in various settings. By gene expression profiling of a leukemic stem cell-enriched cell population in acute myeloid leukemia, we could identify a set of genes that is highly predictive for clinical prognosis. Our studies focusing on nucleophosmin-mutated acute myeloid leukemia demonstrate that MEIS1 is an important target gene for this leukemia. Moreover, we argue to use both immunohistochemical and molecular techniqus in the detection of nucleophosmin mutations, since information can be missed if only one technique is used. Given that acute myeloid leukemia is merely a disease of the elderly and age-related effects could be a factor in leukemic development, we studied the effects of increasing age on the bone marrow of healthy individuals. The results suggest that age-related changes may not be functionally relevant in steady state conditions but can become apparent in situations of chemotoxic and replicative stress. Studying bone marrow stem and progenitor cells in patients one year following autologous stem cell transplantation revealed significant long-term effects of the transplantation, including a changed progenitor composition, a higher cycling activity and persistent gene expression changes. These effects may explain the increased vulnerability to chemotherapy, which is an important clinical concern in patients following autologous transplantation.