Tackling acute myeloid leukemia: Characterization and modulation of the hematopoietic epigenome

TY - THES

T1 - Tackling acute myeloid leukemia: Characterization and modulation of the hematopoietic epigenome

AU - Wiggers, Caroline Rebecca Marcellina

PY - 2020/1/14

Y1 - 2020/1/14

N2 - The research described in this thesis contributes to the understanding of the mechanisms involved in the recurrence of acute myeloid leukemia in children and adults after treatment (AML relapse). We analyzed active regions in the genome using epigenetics, as this is a highly sensitive method to identify differences between cell types and is useful to unravel which processes are responsible for these differences. By analyzing the epigenome we identified several genes that showed higher activity in children that suffered from AML relapse. These genes can be used to classify patients already at initial diagnosis for their relapse risk. Importantly, distinct sets of these genes were clinically relevant for different groups of AML patients. This is important information for better risk profiling of patients which could lead to better treatment strategies. In addition to these results, we have identified a new potential therapeutic drug for the treatment of children with AML. Treatment with this drug, NSC3852, influences the epigenome by increasing the activity on DNA regions that are normally inactive. Our results from the lab showed that NSC3852 treatment effectively killed AML cells while relatively sparing normal blood cells. Finally, we analyzed the effect of two existing drugs, entinostat and vorinostat, that influence the epigenome similar as NSC3852, on normal blood cells in the lab. These results provide important insight into the influence of treatment with these drugs on normal blood cells which is necessary to avoid unwanted side effects.

AB - The research described in this thesis contributes to the understanding of the mechanisms involved in the recurrence of acute myeloid leukemia in children and adults after treatment (AML relapse). We analyzed active regions in the genome using epigenetics, as this is a highly sensitive method to identify differences between cell types and is useful to unravel which processes are responsible for these differences. By analyzing the epigenome we identified several genes that showed higher activity in children that suffered from AML relapse. These genes can be used to classify patients already at initial diagnosis for their relapse risk. Importantly, distinct sets of these genes were clinically relevant for different groups of AML patients. This is important information for better risk profiling of patients which could lead to better treatment strategies. In addition to these results, we have identified a new potential therapeutic drug for the treatment of children with AML. Treatment with this drug, NSC3852, influences the epigenome by increasing the activity on DNA regions that are normally inactive. Our results from the lab showed that NSC3852 treatment effectively killed AML cells while relatively sparing normal blood cells. Finally, we analyzed the effect of two existing drugs, entinostat and vorinostat, that influence the epigenome similar as NSC3852, on normal blood cells in the lab. These results provide important insight into the influence of treatment with these drugs on normal blood cells which is necessary to avoid unwanted side effects.

M3 - PhD thesis

PB - Utrecht University

ER -