Role of the haematopoietic stem cell niche in pre-leukemic clonal haematopoiesis and myelodysplatic syndromes

Myelodysplastic syndromes (MDS) are prototype pre-leukemic conditions that initiate in haematopoietic stem cells (HSC). These are characterized by clonal HSC expansion, inefficient production of mature blood cells and a higher propensity to progress to acute myelogenous leukaemia. Multiple studies suggest that MDS-HSCs are highly dependent on the bone marrow niche. It is possible that leukemic stem cells exploit the normal remodelling capacity of the niche to create a self-reinforcing leukemic environment, thereby favouring leukaemia development. However the molecular mechanisms involved in this process are still largely unknown. This project aims at identifying the signalling networks involved in the bidirectional crosstalk between MDS-HSCs and specific niche cells, and how this contributes to MDS pathogenesis in both mouse and human. A multidisciplinary approach will be used, combining transcriptomic analysis of niche cells and HSCs, 3D-imaging of the bone marrow and computational modelling. I will investigate which essential interactions between MDS-HSCs and their niches are responsible for their competitive advantage over normal HSCs. These studies have the goal of ultimately disrupting these interactions as a novel therapeutic avenue for MDS, a disease that currently has very few treatment options.