PhD defence F.M. (Femke) Hormann

Summary:

Leukemia is the most common form of cancer in children. In 85%, the leukemia occurs in developing B-cells, which is called B-cell precursor acute lymphoblastic leukemia. In around 60% of patients, the leukemia cells also have an alteration in chromosome 21. This indicates that chromosome 21 plays a role in leukemia. In this thesis, I studied the relation between alterations in chromosome 21 and B-cell precursor acute lymphoblastic leukemia. I focused specifically on the iAMP21 subtype, a subtype in which large parts of chromosome 21 are amplified, moved, or deleted. I used DNA and RNA sequencing techniques and combined this with laboratory experiments. I found that many samples from leukemia patients with a chromosome 21 alteration have a mutation that could be targeted with specific drugs. Furthermore, I found that leukemic cells of iAMP21 patients have a high frequency of JAK/STAT pathway mutations and that they are sensitive to precision medicines in laboratory assays. In addition, I identified the minimal piece of chromosome 21 that is amplified in all studied iAMP21 patients. This piece could be of importance in the development of leukemia in these patients. Finally, I made a leukemia cell line that has an extra copy of chromosome 21. Such a cell line did not exist, and the cell line I created could be used to study the relation between chromosome 21 and leukemia. My research and the models I developed, will help further research into improved treatment of this disease.