14 January 2020 Thesis defense Caroline Wiggers: Tackling acute myeloid leukemia Back to news Caroline Wiggers, from the group of Menno Creyghton at the Hubrecht Institute and also under supervision of pediatric hematologist Marije Bartels from the UMC Utrecht (Wilhelmina Children’s Hospital), successfully defended her thesis “Tackling acute myeloid leukemia: characterization and modulation of the hematopoietic epigenome” on the 14th of January. During her PhD, Wiggers characterized the epigenetic landscape of cancer cells in acute myeloid leukemia and normal hematopoietic cells in an effort to better understand this devastating disease and help develop more effective treatments in de future. Schematic representation of acute myeloid leukemia initiation and relapse. Copyright Caroline Wigggers Acute myeloid leukemia (AML) is a form of blood cancer. In AML, the stem and progenitor cells of the blood divide in an uncontrolled way and they fail to differentiate into mature blood cells, such as red blood cells and immune cells. Because of this, the blood is filled with these cancerous blood cells, leaving insufficient space for normal differentiated cells. After chemotherapy, leukemic cells are no longer detectable in around 90% of children with AML. However, around 30-40% of these children will relapse, meaning that the cancer comes back. AML relapse is difficult to treat and only around 25-40% of the children survive after relapse. Therefore, it is necessary to better understand the disease and develop more effective treatments. Epigenetic processes during the differentiation of blood cells. Copyright Caroline Wiggers Promoters and enhancers AML can be caused by mutations in the DNA, and/or by deregulation of the activity of genes. The activity of genes can be influenced by regulatory pieces of DNA. Among these regulatory DNA elements are promoters and enhancers, both of which can influence the activity of a gene. In different types of cells, different promoters and enhancers are active and are marked with a modification, or a label, called H3K27ac. This label is deposited, erased and read by different proteins. A misregulation of these proteins can result in a mislabeling of regulatory DNA elements. This in turn can result in mistakes in the activity of genes and may lead to disease. Relapse Wiggers characterized which promoters and enhancers are active in children with AML by measuring the H3K27ac modification and found differences between children that have relapsed compared to those who have not. She found that these promoters and enhancers deregulate the activity of certain genes already at the moment of diagnosis in those children in which the cancer will come back. Therefore, the activity of these genes may be used at the time of diagnosis to identify those children with a high risk of relapse. In addition, knowing which genes are misregulated in relapsed children can help to better understand the mechanisms involved in relapse. Subgroups Wiggers also found that there are defined subgroups of patients within the group of patients that relapse. For each of these subgroups, different genes were clinically relevant. This means that there are likely different mechanisms that can lead to relapse across different patient subgroups. In order to use this finding in the clinic to better predict relapse risk, we need to study and treat patient subgroups separately. Treatment with the potential new drug NSC3852 (right) induces differentiation of AML cells when compared to AML cells that were not treated with the drug (left). Copyright Caroline Wiggers New drugs Specialized drugs exist that may help treat patients with AML, because these drugs can block the activity of the writers, readers or erasers that normally modify the labels and thereby regulate the activity of regulatory DNA, such as the H3K27ac label on promoters and enhancers. Wiggers conducted a large screen with such drugs to test if there are drugs that can specifically kill the AML cells, while leaving the normal cells unaffected. She found one drug that specifically targeted AML cells, while normal differentiating blood cells were less susceptible. This drug, NSC3852, blocks the removal of the H3K27ac label on promoters and enhancers. AML cells responded by dividing less frequently, dying and differentiating. This drug may be a potential new drug for children with AML. Before this drug can be tested in clinical trials however, additional pre-clinical experiments should be conducted. A new technique In addition to her research on AML, Wiggers developed a new technique, called ATAC-STARR-seq, to quantitatively measure the activity of regulatory DNA elements genome-wide. In the future, this technique may be used to identify regulatory DNA elements that play an important role in AML. This may help to identify and further study the mechanisms underlying AML and AML relapse. During her PhD, Caroline Wiggers worked in the group of Menno Creyghton at the Hubrecht Institute and under supervision of pediatric hematologist Marije Bartels at the UMC Utrecht (Wilhelmina Children’s Hospital). After her defense, she will move to Boston to start her postdoctoral research in the lab of Birgit Knoechel at the Dana-Farber Cancer Institute at Harvard Medical School.
