23A. A life without blood: Single-cell analysis of childhood myelodysplastic syndrome to uncover therapeutic targets

Short description of project

Pediatric myelodysplastic syndrome (MDS) is a premalignant, clonal disorder of hematopoietic stem cells (HSCs). Children with MDS have ineffective blood cell production and a high risk of acute myeloid leukemia (AML). Their only curative option consists of high-dose chemotherapy followed by allogeneic hematopoietic stem cell transplantation. However, this therapy has substantial short-term and long-term toxicity. 5-10% of children with MDS die as a result of treatment-related complications. Thus, there is an unmet need for effective, less toxic strategies to cure pediatric MDS and/or to prevent leukemic evolution. However, the development of such strategies is hampered by insufficient understanding of the pathogenesis of pediatric MDS/AML.

This project aims to dissect the cellular/molecular mechanisms underlying pediatric MDS and its progression towards AML. Our lab specializes in (single-cell) analysis of human HSCs, using RNA-sequencing and multi-omics. Here, we will apply these state-of-the-art technologies to healthy and patient-derived bone marrow samples, to identify genes, pathways or interactions that are aberrant in children with MDS. Subsequently, we will use in vitro HSC (co-)cultures to model and manipulate these features. Finally, we will exploit 3D imaging to dissect the spatial architecture of the MDS bone marrow compartment. By doing so, we aim to identify potential targets to treat pediatric MDS and/or to prevent its progression towards leukemia. In summary, the selected candidate will be trained as a multidisciplinary scientist with know-how in single-cell sequencing, tissue culture, imaging and translational science.

The team

The Belderbos lab is an inclusive team, consisting of people from diverse backgrounds and with complimentary expertise. We are embedded in the Princess Máxima Center disease committee for myeloid malignancies and stem cell disorders, ensuring close collaborations with international experts and access to a large number of facilities. Core values in our lab are collaboration, curiosity and clinical impact.