Katrin Ottersbach Research Group | Centre for Regenerative Medicine

Developmental origins of blood stem cells and leukaemia

Blood stem cells have the ability to produce every blood cell type and are therefore of immense clinical importance. Our group investigates how these cells are first generated during foetal development, how they can be maintained and what their unique properties are. A further interest of our group is how these early blood cells are targeted by mutations that can lead to cancer development in infant patients.

Professor Katrin Ottersbach

Professor of Developmental Haematology / Cancer Research UK Fellow

Contact details

Microscopy images of haematopoietic cells in the mouse embryonic dorsal aorta — Haematopoietic cells in the mouse embryonic dorsal aorta (E11.5). Left: expression of three microenvironmental regulators of haematopoietic stem cell emergence. Right: clusters of emerging ckit haematopoietic cells

Aims and areas of interest

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.

Our previous work has established that the transcription factor Gata3 plays a crucial role during the generation of HSCs, both cell-intrinsically as well as through effects on the microenvironment (e.g. catecholamine production). We continue to dissect the molecular mechanisms underlying its multi-facetted role.

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 KMT2A (MLL) locus as these have a particularly poor prognosis. We have identified and characterised foetal-specific expression programmes that are hijacked by the KMT2A fusion oncogenes to drive an early-onset, aggressive disease. We have also been successful in generating representative mouse models for infant acute lymphoblastic, acute myeloid and mixed phenotype acute leukaemia in which early events and involvement of the microenvironment can be studied. The overall aim is to identify more specific therapeutic targets and kinder treatments for this vulnerable group of patients.