High levels of vitamin C absorbed by blood-forming stem cells are important for their normal development.

Ascorbate, also known as vitamin C, plays a key role in determining whether blood-forming stem cells will become cancerous, according to a study of cell cultures and mice published today (August 21) in Nature.

Both human and mouse hematopoietic stem cells are flush with high levels of ascorbate that progressively decrease as the cells develop, the scientists found. Using mice genetically deficient in gulonolactone oxidase—the enzyme the animals need to synthesize vitamin C—the team demonstrated that ascorbate suppresses leukemia progression while ascorbate deficiencies can accelerate cancer’s development.

Leukemia

 

“Stem cells need ascorbate to regulate gene expression. They soak up higher levels of ascorbate than other cells,” says coauthor Sean Morrison, director of the University of Texas Southwestern Children’s Medical Center Research Institute. “Our data begin to explain the longstanding epidemiological evidence for why humans with lower vitamin C levels get more cancer.”

The researchers also found that depleting ascorbate drives leukemia in mice by impinging on the function of TET2, a DNA demethylation enzyme important for normal stem cell development. TET2 mutations are common in patients with leukemia. “If you don’t have normal, high ascorbate levels, then ascorbate is limiting for TET function in vivo,” he says.

“TET is really important. . . . Anything that’s going to interfere with TET2, particularly in hematopoietic stem cells which give rise to leukemia, could be a problem,” says Stephen Baylin, a cancer biologist at John Hopkins University’s Sidney Kimmel Comprehensive Cancer Center who was not involved in the study.

Vitamin C converts iron into a state that can be used by TET2 as it works to demethylate DNA, Benjamin Neel, director of the Perlmutter Cancer Center at New York University Langone Health, told The Scientist last week. Last Thursday (August 17), Neel and his colleagues independently determined that high doses of vitamin C can block leukemia development in mice with engineered TET2 deficiencies.

See “Vitamin C Blocks Leukemia Progression in Mice”

When Morrison and colleagues fed gulonolactone oxidase-deficient mice low levels of ascorbate to recapitulate those seen in vitamin C–deficient individuals, the mice developed abnormal blood cells and leukemia-consistent DNA signatures within their hematopoietic stem cells, suggesting TET2 malfunction. Notably, the researchers showed that these symptoms could be avoided by increasing ascorbate levels in the mice’s diets.

These studies are complementary, and taken together, demonstrate that vitamin C is necessary for normal hematopoietic stem cells function “and to maintain full activity of the TET enzymes,” Luisa Cimmino, an assistant professor of pathology at NYU Langone Health and lead author on Neel’s paper, tells The Scientist in an email.

“For patients at a greater risk of developing leukemia or with leukemia,” she says, enhancing and ensuring the normal function of TET2 could “be preventative and of therapeutic benefit.”

Morrison stresses that, according to these studies, maintaining normal levels of vitamin C are important for cancer prevention. “Our work shows that getting your 100% daily requirement of vitamin C is important, but our work doesn’t provide any evidence that megadoses of vitamin C would provide any added benefit.” Human trials are still needed to confirm these effects.