Abstract
Elevated ascorbate levels maintain TET2 activity in HSCs and decline with differentiation.
Major finding: Elevated ascorbate levels maintain TET2 activity in HSCs and decline with differentiation.
Concept: Ascorbate depletion cooperates with FLT3ITD to promote myelopoiesis, HSC function, and leukemogenesis.
Impact: Adequate dietary ascorbate may be necessary to maintain the tumor suppressive function of TET2.
Metabolites can alter stem cell fate in vitro, but it is not clear if physiologic changes in metabolites are sufficient to alter stem cell function in vivo. Agathocleous and colleagues developed a method for metabolomics analysis in rare cell populations using rapid cell isolation by flow cytometry combined with liquid chromatography/mass spectrometry. This approach allowed detection of metabolites in hematopoietic stem cells (HSC) and multipotent progenitors (MPP) from mouse bone marrow and revealed that ascorbate (vitamin C) was enriched compared with other hematopoietic progenitors, and ascorbate levels declined with differentiation as did expression of the ascorbate transporter Slc23a2. Ascorbate is a cofactor for several α-ketoglutarate–dependent dioxygenases including TET2, which promotes DNA demethylation by catalyzing the conversion of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC). Accordingly, ascorbate depletion suppressed TET2 activity and 5hmC in HSCs and MPPs in vivo. This resulted in an increase in HSC frequency and function following ascorbate depletion. Although TET2 was responsible for most of the 5hmC reduction in ascorbate-depleted HSCs and MPPs, ascorbate depletion also reduced 5hmC levels in Tet2-deficient mice, suggesting an additional TET2-independent effect, possibly mediated by TET1 or TET3. TET2 mutations can promote acute myeloid leukemia together with FLT3ITD mutations, and ascorbate depletion recapitulated TET2 deficiency, cooperating with Flt3ITD mutations to promote myelopoiesis, cell-autonomously enhance HSC function, and accelerate leukemogenesis in vivo. Further, in mice with ascorbate-depleted leukemia, dietary ascorbate extended survival, reduced myeloblasts in the blood, and decreased HSC frequency in the spleen. Similarly, human HSCs had elevated ascorbate levels and SLC23A2 expression, suggesting that these findings may be applicable to humans. Altogether, these data indicate that ascorbate accumulation in HSCs promotes TET2 function to suppress leukemogenesis, and suggest that dietary ascorbate may be necessary for maximal tumor suppressive function of TET2.
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