Leukaemia & Lymphoma Research Bennett Senior Fellow

PI Photo

Email: ko268@cam.ac.uk

Research themes:

Developmental Haematopoiesis, Infant Leukemia

Description of research

The Developmental Origins of Haematopoietic Stem Cells

Haematopoietic stem cells (HSCs) have been intensely studied for many decades as a model system for stem cell biology. Our work focuses on the emergence and regulation of the first haematopoietic stem and progenitor cells in the mouse embryo in order to identify the basic mechanisms that control their generation from precursors and their initial expansion and dissemination to the different haematopoietic organs. Knowledge of these early regulatory pathways has proven to be invaluable for understanding how HSCs may be generated from ES or iPS cells, how adult HSCs can be manipulated for clinical purposes and how interference with these processes may result in blood-related disorders. Part of our lab studies specifically how embryonic blood cells can be the target for transformation in a particularly severe type of infant leukaemia. Our research therefore complements that of several groups within the University which also work on various aspects of normal and leukaemic stem cell biology.

A recent focus of our research has been the microenvironment that controls the emergence, expansion and dissemination of HSCs and how it may contribute to leukaemogenesis. In this context, we have uncovered a functional link between the developing haematopoietic and sympathetic nervous system, have identified the first negative regulator of emerging HSCs and have started dissecting the relevant cytokine pathways. We are now in the process of identifying the cell types that are part of this microenvironment and revealing the specific function they perform.

Current post-docs: Simon Fitch, Camille Malouf

Research focus

Keywords: Developmental Haematopoiesis, Haematopoietic Stem Cells, Aorta-Gonads-Mesonephros (AGM) Region, Microenvironment

Clinical conditions: Infant Leukaemia

Methodologies: Gene Expression Analysis, Haematopoietic Stem and Progenitor Cell Assays, Histology

H-Index: 16

Cambridge collaborators

Bertie Gottgens, Tony Green, Brian Huntly, Anton Enright

Other collaborators

John Pimanda, Alexander Medvinsky, Charles Durand, Pierre Charbord, Sten Eirik Jacobsen, Tom Milne

Key Publications

  • Mirshekar-Syahkal B., Haak E., Kimber G.M., van Leusden K., Harvey K., O’Rourke J., Laborda J., Bauer S.R., de Bruijn M.F.T.R., Ferguson-Smith A.C., Dzierzak E. & Ottersbach K. (2013) Dlk1 is a negative regulator of emerging hematopoietic stem and progenitor cells. Haematologica 98:163-171
  • Fitch, S.R., Kimber G., Wilson N.K., Parker A., Mirshekar-Syahkal B., Göttgens B., Medvinsky A., Dzierzak E. & Ottersbach K. (2012) Signaling from the sympathetic nervous system regulates hematopoietic stem cell emergence during embryogenesis. Cell Stem Cell 11:554-566
  • Mascarenhas M.I., Parker A., Dzierzak E. & Ottersbach K. (2009) Identification of novel regulators of hematopoietic stem cell development through refinement of stem cell localization and expression profiling. Blood 114:4645-53
  • Ottersbach K. & Dzierzak E. (2005) The Murine Placenta Contains Hematopoietic Stem Cells within the Vascular Labyrinth Region. Developmental Cell 8: 377-87