Projektbeschreibung
Aneuploidie und Leukämie – worin besteht die Verbindung?
Bei Kindern mit Down-Syndrom ist das Risiko für akute Leukämie um das 500-Fache erhöht. Die genauen Mechanismen, die die Ansammlung von Mutationen in hämatopoetischen Zellen bei vom Down-Syndrom Betroffenen beeinflussen, sind jedoch weitgehend unbekannt. Das vom Europäischen Forschungsrat finanzierte Projekt CONTEXT zielt darauf ab, die Auswirkungen von Aneuploidie auf die Blutbildung sowie die Entstehung und Ansammlung von Mutationen zu erforschen. Anhand von Mutations- und Transkriptomanalysen in hämatopoetischen Vorläuferzellen der fetalen Leber von Gesunden und von Menschen mit Down-Syndrom werden die Forschenden die Mechanismen der durch Aneuploidie verursachten Leukämieentstehung untersuchen. Die Projektergebnisse werden wichtige Erkenntnisse über die Entwicklungsprozesse im gesunden Körper und bei Krankheiten liefern.
Ziel
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.
Wissenschaftliches Gebiet
Programm/Programme
- HORIZON.1.1 - European Research Council (ERC) Main Programme
Thema/Themen
Finanzierungsplan
HORIZON-AG - HORIZON Action Grant Budget-BasedGastgebende Einrichtung
1165 Kobenhavn
Dänemark