The accumulation of mistakes in the DNA of healthy blood (stem) cells can result in acute myeloid leukemia (AML). In addition, multiple subclones can co-exist within one AML patient, each with distinct combinations of DNA alterations. In this thesis we identified 50 leukemia-enriched proteins expressed on the outer cell layer of the leukemia (stem) cells. With these proteins, we are able to identify, isolate and study distinct subclones within one AML patient. We show that these AML subclones have different cell biological properties, and thereby differ in their sensitivity towards certain medication. A mouse model is one of the possible ways to study the properties of leukemia cells. We previously developed, with the use of human stromal stem cells, a human bone marrow environment in mice. Herein we can inject leukemia cells and study important interactions with the human bone marrow environment. In this thesis, we studied the effect of two important human growth factors on leukemia cells within this humanized mouse model. Finally, we studied the function of one of the leukemia-specific proteins in more detail. We showed that this protein plays a central role in the formation and maintenance of an inflammatory bone marrow environment. This inflammatory environment affects healthy blood (stem) cells, whereas the AML cells are not affected. Improving the models in which we can study leukemia cells, identification of leukemia-enriched proteins, detailed knowledge of these proteins and further unraveling cell biological properties of distinct AML subclones will improve patient-specific therapy.
|Qualification||Doctor of Philosophy|
|Place of Publication||[Groningen]|
|Publication status||Published - 2020|