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Aneuploidy and Its Impact on Blood Development: Context Matters

Descrizione del progetto

Scoprire il legame tra aneuploidia e leucemia

I bambini affetti da sindrome di Down sono soggetti a una possibilità 500 volte maggiore di sviluppare leucemia acuta rispetto agli altri. Ciononostante, i precisi meccanismi che influiscono sull’acquisizione delle mutazioni nelle cellule ematopoietiche in questa sindrome sono poco compresi. Il progetto CONTEXT, finanziato dal Consiglio europeo della ricerca, intende approfondire l’impatto esercitato dall’aneuploidia sulla formazione del sangue, nonché sull’insorgenza e sull’accumulo di mutazioni. I ricercatori svolgeranno un’analisi mutazionale e trascrittomica in progenitori ematopoietici presenti nel fegato fetale con e senza sindrome di Down allo scopo di chiarire il meccanismo alla base della generazione di leucemia causata da aneuploidia. I risultati forniranno importanti indizi sui meccanismi di sviluppo in condizioni di salute e di malattia.

Obiettivo

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.

Istituzione ospitante

KOBENHAVNS UNIVERSITET
Contribution nette de l'UE
€ 1 999 995,00
Indirizzo
NORREGADE 10
1165 Kobenhavn
Danimarca

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Regione
Danmark Hovedstaden Byen København
Tipo di attività
Higher or Secondary Education Establishments
Collegamenti
Costo totale
€ 1 999 995,00

Beneficiari (1)