Leukaemia

Vitamin C regulates stem cells and cancer

It emerges that high levels of vitamin C in blood-forming stem cells influence the number and function of the cells and affect the development of leukaemia, through binding to a tumour-suppressor protein, Tet2. See Article p.476

The substrates, intermediates and products of cellular metabolism have the potential to influence cellular identity and transformation to cancer1,2. Two papers (one by Agathocleous et al.3 on page 476 and the other by Cimmino et al.4 in Cell) now find a previously unknown role for one such metabolite, vitamin C, in stem-cell biology. They show that levels of vitamin C, also known as ascorbate, regulate the number and function of blood-forming haematopoietic stem cells, largely through effects on the Tet2 protein. This change, in turn, alters the progression of leukaemia.

Researchers' ability to profile metabolites in stem cells has previously been limited by the fact that such analyses typically require millions of cells. Mouse blood cells, for instance, consist of less than 0.01% haematopoietic stem cells (HSCs)5, making it difficult to obtain sufficient numbers for study. Agathocleous et al. overcame this problem by developing a method for analysing metabolites in as few as 10,000 cells. Using this technique, they found clear differences between the metabolic profiles of mouse blood cells at various stages of differentiation.

The authors discovered that levels of vitamin C are between 2 and 20 times higher in populations of immature stem cells and progenitor cells than in more-differentiated cell types. Consistent with this finding, they showed that expression of the gene Slc23a2, which encodes a protein that imports vitamin C, was higher in HSCs than in more-differentiated cells. Importantly, the researchers confirmed their observations in human blood cells.

Agathocleous and colleagues next sought to determine whether vitamin C levels regulate HSC numbers and function. Unlike humans, who cannot synthesize vitamin C and rely entirely on dietary sources, mice produce the enzyme gulonolactone oxidase (Gulo), which generates vitamin C in the liver. Mice lacking the Gulo gene therefore also depend on dietary sources of vitamin C. The authors demonstrated that mice lacking Gulo developed vitamin C deficiency when fed a diet low in the vitamin. These mice had more HSCs than controls, and their HSCs had increased function, as defined by the cells' ability to repopulate the blood system of recipient mice in bone-marrow-transplant experiments.

Vitamin C is a cofactor for the enzyme Tet2 (ref. 6), which regulates the modification of DNA by methyl groups — a regulatory mechanism that can lead to changes in gene expression. Specifically, Tet2 catalyses an intermediate step in DNA demethylation7, converting the molecule 5-methylcytosine to 5-hydroxymethylcytosine (5hmC). Genetic inactivation of Tet2, much like vitamin C depletion, leads to increased HSC numbers8, as well as a block of HSC differentiation. In line with this, Agathocleous et al. found that vitamin C depletion results in decreased levels of 5hmC, suggesting a decrease in Tet2 activity. The authors next compared mice lacking Tet2, Gulo or both, and found only slight differences in 5hmC levels and HSC function between them, implying that the effects of vitamin C depletion are mediated in large part — although not entirely — by Tet2 (Fig. 1).

Figure 1: The effects of vitamin C on stem-cell biology and leukaemia.
figure1

a, Vitamin C is a cofactor for the enzyme Tet2 — interaction between them enables Tet2 to oxidize methyl groups in the modified DNA base methylcytosine (5mC) to produce 5-hydroxymethylcytosine (5hmC), leading to changes in gene expression. Agathocleous et al.3 and Cimmino et al.4 demonstrate that this pathway maintains the normal function of blood-forming haematopoietic stem cells (HSCs). Vitamin C also maintains HSC function through unknown, Tet2-independent mechanisms. b, By contrast, vitamin C depletion leads to impaired 5mC demethylation and expansion of the HSC population owing to excessive self-renewal. This, in turn, increases the potential for HSCs to give rise to leukaemia.

Cimmino et al. reached a similar conclusion by taking an alternative approach. They investigated whether sustained inactivation of Tet2 is required for the increased HSC activity and susceptibility to leukaemia that occurs in mice completely lacking Tet2, by generating mice in which Tet2 could be depleted and then restored. Restoration of Tet2 expression in these animals reversed the enhanced HSC function and block of HSC differentiation caused by Tet2 loss. The researchers next demonstrated that they could achieve the same effect pharmacologically, using vitamin C to restore Tet2 activity in vitro and in vivo. The treatment led to higher 5hmC levels, to reduced HSC self-renewal and to a partial reversal of the differentiation defects seen in Tet2-mutant animals.

Tet2 mutations are common in acute myeloid leukaemia (AML) in humans9. Both groups therefore examined the effects of vitamin C on this cancer. Agathocleous et al. made use of a mouse model in which AML is driven by two mutations — Tet2 inactivation and overexpression of the gene FLT3-ITD (a mutation found in 20–30% of human cases of AML)10. The authors found that depletion of vitamin C accelerated the growth of these leukaemias, partially owing to impairment of Tet2 function. This effect could be reversed with dietary vitamin C.

Cimmino et al. used AML cells taken from humans, which they studied in vitro or transplanted into mice. In both cases, vitamin C supplementation induced differentiation and the death of leukaemia cells. In mice, these changes led to decreased rates of AML progression.

The effect of vitamin C on human health in general, and on cancer in particular, has been a subject of debate since the 1970s. Epidemiological studies have found varied associations between low vitamin C and decreased overall survival and deaths related to both cardiovascular disease and cancer11,12. By contrast, clinical trials of cancer treatments have provided no evidence that vitamin C supplements have beneficial effects on tumour growth or survival13. One explanation for this discrepancy might be that vitamin C supplementation is efficacious only in people truly deficient in vitamin C, a group that represents just 7% of the US population14.

Vitamin C and Tet2 function have previously been linked to inflammation, a condition also associated with altered stem-cell function, cardiovascular disease and cancer risk15,16. Indeed, our group and others have defined a clinical state in which mutations — commonly including TET2 — that arise in HSCs are prevalent in the blood systems of healthy individuals. This state increases in frequency with age (increasing to more than 10% in people over 70)17, causes inflammation and is associated with a significantly increased risk of both cardiovascular disease and the development of leukaemia18.

The current studies provide support for the hypothesis that vitamin C deficiency alters HSC function and may influence the risk of leukaemia and other diseases. In the future, large-scale population studies that include comprehensive clinical, genomic and metabolic data may define therapeutically relevant associations between vitamin C and cancer, cardiovascular disease and death. Such studies could prove particularly useful in further defining the relationship between Tet2 mutations, vitamin C, inflammation and cancer.

Lemons will probably not do for leukaemia what they did for scurvy. Nonetheless, we are a step closer to understanding what makes stem cells, both normal and cancerous, tick.Footnote 1

Notes

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Correspondence to Benjamin L. Ebert.

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Miller, P., Ebert, B. Vitamin C regulates stem cells and cancer. Nature 549, 462–464 (2017). https://doi.org/10.1038/nature23548

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