Houston, Texas, USA : Vitamin C may “tell” faulty stem cells in the bone marrow to mature and die normally, instead of multiplying to cause blood cancers. This is the finding of a study led by researchers from Perlmutter Cancer Center at NYU Langone Health, and published in the journal Cell.
Certain genetic changes are known to reduce the ability of an enzyme called TET2 to encourage stem cells to become mature blood cells, which eventually die, in many patients with certain kinds of leukemia, say the authors. The new study found that vitamin C activated TET2 function in mice engineered to be deficient in the enzyme.
“We’re excited by the prospect that high-dose vitamin C might become a safe treatment for blood diseases caused by TET2-deficient leukemia stem cells, most likely in combination with other targeted therapies,” says corresponding study author Benjamin G. Neel, MD, PhD, professor in the Department of Medicine and director of the Perlmutter Cancer Center.
Changes in the genetic code (mutations) that reduce TET2 function are found in 10 percent of patients with acute myeloid leukemia (AML), 30 percent of those with a form of pre-leukemia called myelodysplastic syndrome, and in nearly 50 percent of patients with chronic myelomonocytic leukemia. Such cancers cause anemia, infection risk, and bleeding as abnormal stem cells multiply in the bone marrow until they interfere with blood cell production, with the number of cases increasing as the population ages.
Along with these diseases, new tests suggest that about 2.5 percent of all U.S. cancer patients – or about 42,500 new patients each year – may develop TET2 mutations, including some with lymphomas and solid tumors, say the authors.
Cell Death Switch
The study results revolve around the relationship between TET2 and cytosine, one of the four nucleic acid “letters” that comprise the DNA code in genes. Every cell type has the same genes, but each gets different instructions to turn on only those needed in a given cellular context.
These “epigenetic” regulatory mechanisms include DNA methylation, the attachment of a small molecule termed a methyl group to cytosine bases that shuts down the action of a gene containing them.
The back- and-forth attachment and removal of methyl groups also fine-tunes gene expression in stem cells, which can mature, specialize and multiply to become muscle, bone, nerve, or other cell types. This happens as the body first forms, but the bone marrow also keeps pools of stem cells on hand into adulthood, ready to become replacement cells as needed. In leukemia, signals that normally tell a blood stem cell to mature malfunction, leaving it to endlessly multiply and “self-renew” instead of producing normal white blood cells needed to fight infection.
The enzyme studied in this report, Tet methylcytosine dioxygenase 2 (TET2), enables a change in the molecular structure (oxidation) of methyl groups that is needed for them to be removed from cytosines. This “demethylation” turns on genes that direct stem cells to mature, and to start a count-down toward self-destruction as part of normal turnover. This serves as an anti-cancer safety mechanism, one that is disrupted in blood cancer patients with TET2 mutations, says Neel.
To determine the effect of mutations that reduce TET2 function in abnormal stem cells, the research team genetically engineered mice such that the scientists could switch the TET2 gene on or off.
Similar to the naturally occurring effects of TET2 mutations in mice or humans, using molecular biology techniques to turn off TET2 in mice caused abnormal stem cell behavior. Remarkably, these changes were reversed when TET2 expression was restored by a genetic trick. Previous work had shown that vitamin C could stimulate the activity of TET2 and its relatives TET1 and TET3. Because only one of the two copies of the TET2 gene in each stem cell is usually affected in TET2-mutant blood diseases, the authors hypothesized that high doses of vitamin C, which can only be given intravenously, might reverse the effects of TET2 deficiency by turning up the action of the remaining functional gene.
Indeed, they found that vitamin C did the same thing as restoring TET2 function genetically. By promoting DNA demethylation, high-dose vitamin C treatment induced stem cells to mature, and also suppressed the growth of leukemia cancer stem cells from human patients implanted in mice.
“Interestingly, we also found that vitamin C treatment had an effect on leukemic stem cells that resembled damage to their DNA,” says first study author Luisa Cimmino, PhD, an assistant professor in the Department of Pathology at NYU Langone Health. “For this reason, we decided to combine vitamin C with a PARP inhibitor, a drug type known to cause cancer cell death by blocking the repair of DNA damage, and already approved for treating certain patients with ovarian cancer.”
Researchers found that the combination had an enhanced effect on leukemia stem cells, further shifting them from self-renewal back toward maturity and cell death. The results also suggest that vitamin C might drive leukemic stem cells without TET2 mutations toward death, says Cimmino, given that it turns up any TET2 activity normally in place.
“Our team is working to systematically identify genetic changes that contribute to risk for leukemia in significant groups of patients,” says corresponding author Iannis Aifantis, PhD, professor and chair of the Department of Pathology at NYU Langone Health. “This study adds the targeting of abnormal TET2-driven DNA demethylation to our list of potential new treatment approaches.”
A second study found that vitamin C regulates stem cell function and it curbs leukemia development.
Scientists discover vitamin C regulates stem cell function, curbs leukemia development
Not much is known about stem cell metabolism, but a new study from the Children’s Medical Center Research Institute at UT Southwestern (CRI) has found that stem cells take up unusually high levels of vitamin C, which then regulates their function and suppresses the development of leukemia.
“We have known for a while that people with lower levels of ascorbate (vitamin C) are at increased cancer risk, but we haven’t fully understood why. Our research provides part of the explanation, at least for the blood-forming system,” said Dr. Sean Morrison, the Director of CRI.
The metabolism of stem cells has historically been difficult to study because a large number of cells are required for metabolic analysis, while stem cells in each tissue of the body are rare. Techniques developed during the study, which was published in Nature, have allowed researchers to routinely measure metabolite levels in rare cell populations such as stem cells.
The techniques led researchers to discover that every type of blood-forming cell in the bone marrow had distinct metabolic signatures – taking up and using nutrients in their own individual way. One of the main metabolic features of stem cells is that they soak up unusually high levels of ascorbate. To determine if ascorbate is important for stem cell function, researchers used mice that lacked gulonolactone oxidase (Gulo) – a key enzyme that most mammals, including mice but not humans, use to synthesize their own ascorbate.
Loss of the enzyme requires Gulo-deficient mice to obtain ascorbate exclusively through their diet like humans do. This gave CRI scientists strict control over ascorbate intake by the mice and allowed them to mimic ascorbate levels seen in approximately 5 percent of healthy humans. At these levels, researchers expected depletion of ascorbate might lead to loss of stem cell function but were surprised to find the opposite was true – stem cells actually gained function. However, this gain came at the cost of increased instances of leukemia.
“Stem cells use ascorbate to regulate the abundance of certain chemical modifications on DNA, which are part of the epigenome,” said Dr. Michalis Agathocleous, lead author of the study, an Assistant Instructor at CRI, and a Royal Commission for the Exhibition of 1851 Research Fellow. “The epigenome is a set of mechanisms inside a cell that regulates which genes turn on and turn off. So when stem cells don’t receive enough vitamin C, the epigenome can become damaged in a way that increases stem cell function but also increases the risk of leukemia.”
This increased risk is partly tied to how ascorbate affects an enzyme known as Tet2, the study showed. Mutations that inactivate Tet2 are an early step in the formation of leukemia. CRI scientists showed that ascorbate depletion can limit Tet2 function in tissues in a way that increases the risk of leukemia.
These findings have implications for older patients with a common precancerous condition known as clonal hematopoiesis. This condition puts patients at a higher risk of developing leukemia and other diseases, but it is not well understood why certain patients with the condition develop leukemia and others do not. The findings in this study might offer an explanation.
“One of the most common mutations in patients with clonal hematopoiesis is a loss of one copy of Tet2. Our results suggest patients with clonal hematopoiesis and a Tet2 mutation should be particularly careful to get 100 percent of their daily vitamin C requirement,” Dr. Morrison said. “Because these patients only have one good copy of Tet2 left, they need to maximize the residual Tet2 tumor-suppressor activity to protect themselves from cancer.”
Researchers in the Hamon Laboratory for Stem Cell and Cancer Biology, in which Dr. Morrison is also appointed, intend to use the techniques developed as part of this study to find other metabolic pathways that control stem cell function and cancer development. They also plan to further explore the role of vitamin C in stem cell function and tissue regeneration.
Citation for second study: Michalis Agathocleous et al. Ascorbate regulates haematopoietic stem cell function and leukaemogenesis, Nature. DOI: 10.1038/nature23876
Video: Researchers from Perlmutter Cancer Center at NYU Langone Health discuss their discovery that vitamin C may “tell” faulty stem cells in the bone marrow to mature and die normally, instead of multiplying to cause blood cancers.
Video credit : NYU Langone Health