Ascorbate regulates haematopoietic stem cell function and leukaemogenesis

Stem cell fate can be influenced by metabolite levels in culture but it is unknown whether physiological variations in metabolite levels in normal tissues regulate stem cell function in vivo. 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 ascorbate depletion in mice increased HSC frequency and function, partly by reducing Tet2 function, a dioxygenase tumor suppressor. Ascorbate depletion cooperated with Flt3(ITD) leukaemic mutations to accelerate leukaemogenesis, though 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 thus accumulates within HSCs to promote Tet function in vivo, limiting HSC frequency and suppressing leukaemogenesis.