Ascorbate regulates stem cell function and leukemogenesis
Stem cell fate can be influenced by metabolite levels in culture but it is unknown whether physiological variations in metabolite levels regulate stem cell function within normal tissues. We developed a metabolomics method for analysis of rare cell populations isolated directly from tissues and used it to compare haematopoietic stem cells (HSCs) to restricted haematopoietic progenitors. Each haematopoietic cell type had a distinct metabolic signature. Human and mouse HSCs had unusually high levels of ascorbate, which declined with differentiation. Systemic or cell autonomous ascorbate depletion in mice increased HSC frequency and function and promoted myelopoiesis. Ascorbate regulated HSC function in part through Tet2, a dioxygenase tumor suppressor enzyme. Ascorbate depletion cooperated with Flt3ITD leukaemic mutations to accelerate leukaemogenesis, and this was reversed by dietary ascorbate. Therefore physiological variations in ascorbate levels in vivo regulate Tet activity, regeneration and leukaemogenesis.
Date: 14 September 2017, 11:00 (Thursday, 21st week, Trinity 2017)
Venue: NDM Building, Headington OX3 7FZ
Venue Details: TDI, Basement meeting room, NDM Research Building
Speaker: Dr Michalis Agathocleous (UT Southwestern)
Organising department: Ludwig Institute for Cancer Research, Oxford Branch
Organisers: Christina Woodward (Oxford Ludwig Institute, Nuffield Department of Medicine, University of Oxford), Mary Muers (Oxford Ludwig Institute, NDM Experimental Medicine)
Organiser contact email address:
Host: Dr Skirmantas Kriaucionis (Ludwig Cancer Research)
Part of: Ludwig Institute Seminar Series
Booking required?: Not required
Audience: Members of the University only
Editor: Mary Muers