“Dissecting the cross-talk between normal, leukaemic stem cells and the bone marrow microenvironment”

Haematopoietic stem cells (HSC) sustain the life-long maintenance of mature blood cells. Over the last decade progress has been made in our understanding of the contribution of the different stroma cells in the regulation of normal HSCs. Our current knowledge is predominantly derived from mouse studies. In humans, the cellular and molecular composition of the bone marrow (BM) niche, its functional organisation remains largely unknown. In recent years, deregulation of the BM microenvironment has emerged to be an important factor in the development of myeloid malignancies. Indeed, like normal HSC, leukaemic stem cells (LSCs) remain dependent on signals from the BM niche for survival and proliferation, and niche factors serves as a sanctuary for their chemoresistance. Thus, targeting BM niche factors represents a promising avenue for therapeutic interventions. Determining the niche associated alterations in the composition/ organisation along with dissecting the interactome of LSCs and their niche is thus fundamental, which will ultimately enable us to understand the mechanism of leukaemia initiation, evolution and resistance.

I will summarise some of the recent published data from the lab, showing the alterations of endothelial cells by AML as well as described the development of our new humanised scaffold system that is allowing us to better study the cross-talk between normal and malignant HSPCs and their bone marrow niche in a human/human context. I will show the utility of this model to study MDS and their dependence to the human niche components. Lastly, I will also discuss new un/published data on the effect of pre-leukaemic mutation on haematopoieisis.