Outsmarting therapy resistant leukemia: Using CRISPR screens for rational design of novel treatment strategies

Abstract

Acute lymphoblastic leukemia (ALL) is the most common form of cancer in children and is characterized by uncontrolled cell division of immature white blood cells in the bone marrow. This rapid expansion prohibits the production of healthy blood cells, resulting in symptoms such as anemia and a dysfunctional immune system, requiring immediate treatment with chemotherapy. The research performed in this thesis focuses on a high-risk group of ALL patients harboring a genetic mutation in the IKZF1 gene. In 10% to 15% of children with ALL one of the two copies of this gene is missing from the DNA. For these children, the chance of a relapse is significantly higher and thereby the survival chances lower. Multiple studies have already shown that these children are less sensitive to steroids such as prednisone, one of the main chemotherapies in the treatment protocol. However, it was unknown whether loss of the IKZF1 gene also results in reduced sensitivity to other chemotherapeutics in the treatment protocol. Therefore, this thesis examined the chemo-response of leukemia cells with an IKZF1 deletion for all therapies in the treatment protocol, revealing that these children are in addition to steroids, also resistant to the drug Cytarabine. Subsequently, we conducted research on a molecular-level using the groundbreaking CRISPR-Cas9 screening technology to understand in depth how the loss of the IKZF1 gene causes resistance to these chemotherapeutics. Finally, we have identified multiple new targeted combination therapies that can overcome resistance to prednisone, AraC or other chemotherapeutics for the treatment of ALL and beyond.