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NEWS & VIEWS doi:10.

1038/nature23548

LE UKAEMIA vitaminC depletion results in decreased levels


of 5hmC, suggesting a decrease in Tet2 activity.

Vitamin C regulates The authors next compared mice lacking


Tet2, Gulo or both, and found only slight dif-
ferences in 5hmC levels and HSC function

stem cells and cancer


between them, implying that the effects of
vitaminC depletion are mediated in large part
although not entirely by Tet2 (Fig.1).
Cimmino et al. reached a similar conclu-
It emerges that high levels of vitamin C in blood-forming stem cells influence sion by taking an alternative approach. They
the number and function of the cells and affect the development of leukaemia, investigated whether sustained inactivation of
through binding to a tumour-suppressor protein, Tet2. Tet2 is required for the increased HSC activ-
ity and susceptibility to leukaemia that occurs
in mice completely lacking Tet2, by generat-
PETER G. MILLER & BENJAMIN L. EBERT depend on dietary sources of vitaminC. The ing mice in which Tet2 could be depleted and
authors demonstrated that mice lacking Gulo then restored. Restoration of Tet2 expression

T
he substrates, intermediates and developed vitaminC deficiency when fed a in these animals reversed the enhanced HSC
products of cellular metabolism have diet low in the vitamin. These mice had more function and block of HSC differentiation
the potential to influence cellular HSCs than controls, and their HSCs had caused by Tet2 loss. The researchers next
identity and transformation to cancer1,2. Two increased function, as defined by the cells abil- demonstrated that they could achieve the
papers (one by Agathocleous etal.3 online in ity to repopulate the blood system of recipient same effect pharmacologically, using vitamin
Nature and the other by Cimmino etal.4 in mice in bone-marrow-transplant experiments. C to restore Tet2 activity invitro and invivo.
Cell) now find a previously unknown role for Vitamin C is a cofactor for the enzyme The treatment led to higher 5hmC levels, to
one such metabolite, vitamin C, in stem-cell Tet2 (ref. 6), which regulates the modifica- reduced HSC self-renewal and to a partial
biology. They show that levels of vitamin C, tion of DNA by methyl groups a regula- reversal of the differentiation defects seen in
also known as ascorbate, regulate the number tory mechanism that can lead to changes in Tet2-mutant animals.
and function of blood-forming haemato gene expression. Specifically, Tet2 catalyses Tet2 mutations are common in acute
poietic stem cells, largely through effects on an intermediate step in DNA demethylation7, myeloid leukaemia (AML) in humans9. Both
the Tet2 protein. This change, in turn, alters converting the molecule 5-methylcytosine to groups therefore examined the effects of
the progression of leukaemia. 5-hydroxymethylcytosine (5hmC). Genetic vitaminC on this cancer. Agathocleous etal.
Researchers ability to profile metabolites inactivation of Tet2, much like vitaminC made use of a mouse model in which AML is
in stem cells has previously been limited by depletion, leads to increased HSC numbers8, driven by two mutations Tet2 inactivation
the fact that such analyses typically require as well as a block of HSC differentiation. In and overexpression of the gene FLT3-ITD (a
millions of cells. Mouse blood cells, for line with this, Agathocleous etal. found that mutation found in 2030% of human cases
instance, consist of less than 0.01% haemato
poietic stem cells (HSCs)5, making it difficult
to obtain sufficient numbers for study. Agatho-
cleous et al. overcame this problem by develop-
a
ing a method for analysing metabolites in as
few as 10,000 cells. Using this technique, they
Vitamin C 5hmC
found clear differences between the metabolic 5mC
TET2
Normal HSC function
profiles of mouse blood cells at various stages
of differentiation.
The authors discovered that levels of DNA
vitaminC are between 2 and 20times higher ?
in populations of immature stem cells and
progenitor cells than in more-differenti-
ated cell types. Consistent with this finding, b
they showed that expression of the gene
Slc23a2, which encodes a protein that imports Increased HSC self-renewal
vitamin C, was higher in HSCs than in Potential for leukaemia
more-differentiated cells. Importantly, the
researchers confirmed their observations in
human blood cells.
Agathocleous and colleagues next sought
to determine whether vitaminC levels regu- Figure 1 | The effects of vitaminC on stem-cell biology and leukaemia. a,Vitamin C is a cofactor for
the enzyme Tet2 interaction between them enables Tet2 to oxidize methyl groups in the modified DNA
late HSC numbers and function. Unlike
base methylcytosine (5mC) to produce 5-hydroxymethylcytosine (5hmC), leading to changes in gene
humans, who cannot synthesize vitaminC expression. Agathocleous etal.3 and Cimmino etal.4 demonstrate that this pathway maintains the normal
and rely entirely on dietary sources, mice function of blood-forming haematopoietic stem cells (HSCs). VitaminC also maintains HSC function
produce the enzyme gulonolactone oxidase through unknown, Tet2-independent mechanisms. b,By contrast, vitaminC depletion leads to impaired
(Gulo), which generates vitaminC in the liver. 5mC demethylation and expansion of the HSC population owing to excessive self-renewal. This, in turn,
Mice lacking the Gulo gene therefore also increases the potential for HSCs to give rise to leukaemia.

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RESEARCH NEWS & VIEWS

of AML)10. The authors found that depletion others have defined a clinical state in which of Medical Oncology, Dana-Farber
of vitaminC accelerated the growth of these mutations commonly including TET2 Cancer Institute, Boston, and at the Broad
leukaemias, partially owing to impairment of that arise in HSCs are prevalent in the blood Institute of MIT and Harvard, Cambridge,
Tet2 function. This effect could be reversed systems of healthy individuals. This state Massachusetts.
with dietary vitamin C. increases in frequency with age (increasing e-mail: bebert@bwh.harvard.edu
Cimmino et al. used AML cells taken from to more than 10% in people over 70)17, causes
1. Dang, L. et al. Nature 462, 739744 (2009).
humans, which they studied invitro or trans- inflammation and is associated with a signifi- 2. Mihaylova, M. M., Sabatini, D. M. & Yilmaz, O. H. Cell
planted into mice. In both cases, vitaminC sup- cantly increased risk of both cardiovascular Stem Cell 14, 292305 (2014).
plementation induced differentiation and the disease and the development of leukaemia18. 3. Agathocleous, M. et al. Nature http://dx.doi.
org/10.1038/nature23876 (2017).
death of leukaemia cells. In mice, these changes The current studies provide support for the 4. Cimmino, L. et al. Cell http://dx.doi.org/10.1016/j.
led to decreased rates of AML progression. hypothesis that vitamin C deficiency alters cell.2017.07.032 (2017).
The effect of vitamin C on human health in HSC function and may influence the risk of 5. Oguro, H., Ding, L. & Morrison, S. J. Cell Stem Cell
13, 102116 (2013).
general, and on cancer in particular, has been leukaemia and other diseases. In the future, 6. Yin, R. et al. J. Am. Chem. Soc. 135, 1039610403
a subject of debate since the 1970s. Epidemio- large-scale population studies that include (2013).
logical studies have found varied associations comprehensive clinical, genomic and meta- 7. Tahiliani, M. et al. Science 324, 930935 (2009).
between low vitaminC and decreased overall bolic data may define therapeutically relevant 8. Moran-Crusio, K. et al. Cancer Cell 20, 1124 (2011).
9. Delhommeau, F. et al. N. Engl. J. Med. 360,
survival and deaths related to both cardiovas- associations between vitaminC and cancer, 22892301 (2009).
cular disease and cancer11,12. By contrast, clini- cardiovascular disease and death. Such stud- 10. Patel, J. P. et al. N.Engl. J. Med. 366, 10791089
cal trials of cancer treatments have provided ies could prove particularly useful in further (2012).
11. Loria, C. M., Klag, M. J., Caulfield, L. E. & Whelton, P. K.
no evidence that vitaminC supplements have defining the relationship between Tet2 muta- Am. J. Clin. Nutr. 72, 139145 (2000).
beneficial effects on tumour growth or sur- tions, vitamin C, inflammation and cancer. 12. Moser, M. A. & Chun, O. K. Int. J. Mol. Sci. 17, 1328
vival13. One explanation for this discrepancy Lemons will probably not do for leukaemia (2016).
13. Lee, B., Oh, S. W. & Myung, S. K. Korean J. Fam. Med.
might be that vitamin C supplementation is what they did for scurvy. Nonetheless, we are a 36, 278285 (2015).
efficacious only in people truly deficient in step closer to understanding what makes stem 14. Schleicher, R. L., Carroll, M. D., Ford, E. S. &
vitaminC, a group that represents just 7% of cells, both normal and cancerous, tick. Lacher, D. A. Am. J. Clin. Nutr. 90, 12521263
(2009).
the US population14. 15. Adams, P. D., Jasper, H. & Rudolph, K. L. Cell Stem
Vitamin C and Tet2 function have Peter G. Miller and Benjamin L. Ebert are Cell 16, 601612 (2015).
previously been linked to inflammation, a in the Division of Hematology, Department 16. Sattar, N. et al. PLoS Med. 6, e1000099 (2009).
condition also associated with altered stem- of Medicine, Brigham and Womens 17. Jaiswal, S. et al. N.Engl. J. Med. 371, 24882498
(2014).
cell function, cardiovascular disease and Hospital, Harvard Medical School, Boston, 18. Jaiswal, S. et al. N.Engl. J. Med. 377, 111121
cancer risk 15,16 . Indeed, our group and Massachusetts 02115, USA, in the Department (2017).

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