Project description
Aneuploidy and leukaemia: what is the link?
Children with Down's Syndrome (DS), have a 500-fold greater chance of developing acute leukaemia. However, the precise mechanisms that influence the acquisition of mutations in hematopoietic cells in DS are poorly understood. Funded by the European Research Council, the CONTEXT project aims to investigate the impact of aneuploidy on blood formation and on the onset and accumulation of mutations. Researchers will undertake mutational and transcriptomic analysis in normal and DS foetal-liver hematopoietic progenitors, to elucidate the mechanism of aneuploidy-driven leukaemia generation. Results will provide important insight into the developmental mechanisms in health and disease.
Objective
Many childhood leukaemias start to develop before birth due to accumulation of mutations during foetal development. Children with trisomy of chromosome 21 (Ts21), also known as Down's Syndrome (DS), have a 500-fold increased chance of developing acute megakaryoblastic leukaemia. It is well known that aneuploidy (an abnormal number of chromosomes) is often associated with leukaemia and is likely to be driving this increased incidence of blood malignancies in children with DS. However, the mechanisms that control differentiation of haematopoietic stem and progenitor cells (HSPCs) and patterns of mutation acquisition in these cells during early human development are not well understood. This study will provide novel insights into two important questions: i) what is the impact of aneuploidy on blood formation in the context of specific tissue and ii) how it affects mutation accumulation and clonal selection in HSPCs. Here I aim to reveal cellular and mutational processes active during human Ts21 foetal blood development by: 1) performing comprehensive single-cell transcriptomics and spatial transcriptomics analysis of human Ts21 and healthy foetal liver and bone marrow combined with single-cell in vitro differentiation assays and 2) generating a catalogue of all somatically-acquired mutations in hundreds of Ts21 foetal haematopoietic progenitors using whole genome sequencing. The approach I propose derives its power from the close integration of state-of-the-art experimental data generation and computational analysis using novel methods. By examining cell intrinsic vs extrinsic processes in Ts21 haematopoiesis as well as mutation accumulation in individual stem cells this study will provide unprecedented insight into the mechanisms by which cellular changes induced by aneuploidy affect and possibly drive leukaemia. A better understanding of early events in human development, in health and disease, will open new routes for diagnosing, monitoring and treating disease.
Fields of science
Programme(s)
- HORIZON.1.1 - European Research Council (ERC) Main Programme
Funding Scheme
HORIZON-AG - HORIZON Action Grant Budget-BasedHost institution
1165 Kobenhavn
Denmark