Ascorbate regulates haematopoietic stem cell function and leukaemogenesis

Abstract

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 Flt3ITD 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.

The impact of cellular metabolism on chromatin dynamics and epigenetics

“…Additionally, metabolites such as S-adenosylhomocysteine (SAH), Coenzyme A (coA), beta-hydroxybutyrate, fumarate, succinate, lactate, and S and R enantiomeric forms of 2-hydroxyglutarate modify enzyme activity often by competitively inhibiting substrate utilization. There is also emerging evidence that vitamin C may act as a cofactor for dioxygenases that modify chromatin and DNA 45–47 . Thus, each modification can be affected by metabolites from multiple metabolic pathways – for instance, enzymes involved in histone and DNA methylation and demethylation can be regulated by both methionine metabolism and the TCA cycle – thus enabling the epigenome to respond to the status of the whole metabolic network.…”

Emerging Applications of Metabolomics in Clinical Pharmacology

“…developed a targeted metabolomics method monitoring ~200 metabolites using a triple quadrupole mass spectrometer coupled to a high‐performance liquid chromatograph. This method has been widely adopted for mechanistic studies of cancer and infectious diseases targeting cell metabolism . In particular, the method is ultrasensitive and can detect ~60 metabolites from only 10,000 hematopoietic stem cells, which enables metabolomics profiling of rare cell populations .…”

Emerging translational science discoveries, clonal approaches, and treatment trends in chronic myeloproliferative neoplasms

“…The influence of the macro‐environment may not be limited to inflammation. As TET enzymes are dioxygenases that require L‐ascorbate (vitamin C) as a cofactor, severe vitamin C deficiency is functionally equivalent to heterozygous TET2 deficiency, implying that poor nutrition may further enhance the outgrowth of TET2 mutant at the expense of WT cells . That CHIP/ARCH is associated with an increased risk of myeloid neoplasms, including MPNs, is intuitive, but the association with increased cardiovascular risk was not suspected .…”