Developmental origins of blood stem cells and leukaemia

One major part of my group's research is to understand how the first haematopoietic stem cells (HSCs) are generated during development and how their subsequent expansion, migration and differentiation are regulated. A particular focus in this context is the identification of the cellular and molecular composition of the microenvironment that facilitates the emergence of HSCs and how this composition changes as HSCs mature and migrate in the developing foetus. The ultimate aim is to dissect out the specific components required for particular HSC functions so that the right conditions can be recreated to achieve HSC generation, expansion and differentiation in vitro. We have recently demonstrated that the transcription factor Gata3 via its role in the sympathetic nervous system is required for HSC production, thus functionally linking these two co-developing systems. We are continuing our studies on how exactly catecholamines, the mediators of the sympathetic nervous system, act on emerging HSCs. We also have evidence that Gata3 performs additional functions during HSC emergence which we are currently investigating.

Embryonic and foetal haematopoietic cells have unique properties with respect to proliferation response and differentiation bias. These are important in the context of HSC expansion and certain types of infant leukaemia that have a prenatal origin, and are another area of interest in the lab. We are particularly interested in infant leukaemias that have chromosomal rearrangements at the MLL locus as these have a particularly poor prognosis. Using MLL-AF4 and MLL-AF9 as examples, our aim is to characterise the foetal-specific context that contributes to disease development and how these oncofusions compromise normal blood development. The overall aim is to identify more specific therapeutic targets and to develop faithful in vivo models in which these can be tested.