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 adult HSCs can be manipulated for clinical purposes and how interference with these processes may result in blood-related disorders. We have recently obtained funding to specifically study 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.

We have recently further defined the region where HSCs are first detected and have incorporated this information into the design of a number of microarray experiments with the aim of identifying novel regulators of HSC generation in the aorta-gonads-mesonephros (AGM) region. Functional validation experiments have revealed a role for the cell cycle regulator p57Kip2 and the growth factor Igf2 in the generation, maintenance and/or migration of the first pool of HSCs. The role of other cytokines in these processes is also being investigated. Furthermore, we have also found evidence that the regulation of HSC generation is influenced by the developing sympathetic nervous system, thus providing a functional link between these two systems in the mouse embryo. We are now in the process of adding an additional level to our expression studies by identifying miRNAs that are essential for developmental haematopoiesis with the aim of defining a network of regulators required for HSC generation.

Current post-docs: Simon Fitch, Camille Malouf

Research focus

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

Clinical conditions: Infant Leukaemia

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

H-Index: 16

Cambridge collaborators

Bertie Gottgens, Tony Green, Anne Ferguson-Smith, Brian Huntly, Anton Enright

Other collaborators

Elaine Dzierzak, Alexander Medvinsky, Marella de Bruijn, Eirik Jacobsen

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