Ascorbate regulates haematopoietic stem cell function and leukaemogenesis

Stem-cell fate can be influenced by metabolite levels in culture, but it is not known whether physiological variations in metabolite levels in normal tissues regulate stem-cell function in vivo . Here we describe a metabolomics method for the analysis of rare cell populations isolated directly from tissues and use it to compare mouse 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 decreased with differentiation. Systemic ascorbate depletion in mice increased HSC frequency and function, in part by reducing the function of Tet2, a dioxygenase tumour suppressor. Ascorbate depletion cooperated with Flt3 internal tandem duplication ( Flt3 ITD ) leukaemic mutations to accelerate leukaemogenesis, through cell-autonomous and possibly non-cell-autonomous mechanisms, in a manner that was reversed by dietary ascorbate. Ascorbate acted cell-autonomously to negatively regulate HSC function and myelopoiesis through Tet2-dependent and Tet2-independent mechanisms. Ascorbate therefore accumulates within HSCs to promote Tet activity in vivo , limiting HSC frequency and suppressing leukaemogenesis. Ascorbate depletion in mice increased haematopoietic stem-cell frequency and promoted leukaemogenesis, partly by reducing the function of the Tet2 tumour suppressor enzyme. Ascorbate levels control blood-cell fate The effect of changes in metabolite levels on stem-cell fate in vivo has been unclear. Sean Morrison and colleagues survey the metabolites of haematopoietic stem cells (HSCs) and progenitors. They show that each type of blood cell has a specific signature and that human and mouse HSCs have high levels of ascorbate, which drop during differentiation. Depletion of ascorbate in mice increases the number and function of HSCs and cooperates with a mutation associated with leukaemia to accelerate tumorigenesis. Analysis of the phenotypes indicates that ascorbate can act in a non-cell-autonomous fashion, partly by modulating the function of the tumour suppressor Tet2.