Early-Phase Study Finds Vitamin C May Activate TET2 Function
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 by Cimmino et al in Cell.
Certain genetic changes are known to reduce the ability of an enzyme called tet methylcytosine dioxygenase 2, or TET2, to encourage stem cells to become mature blood cells, which eventually die, in many patients with certain kinds of leukemia, explained 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,” said corresponding study author Benjamin G. Neel, MD, PhD, Professor in the Department of Medicine and Director of Perlmutter Cancer Center.
Mutations that reduce TET2 function are found in 10% of patients with acute myeloid leukemia (AML), 30% of those with myelodysplastic syndrome, and in nearly 50% of patients with chronic myelomonocytic leukemia. Along with these diseases, new tests suggest that about 2.5% of all American cancer patients—or about 42,500 new patients each year—may develop TET2 mutations, including some with lymphomas and solid tumors.
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. 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. 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.
TET2 enables a change in the molecular structure, or 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 countdown toward self-destruction as part of normal turnover. This serves as an anticancer safety mechanism, one that is disrupted in blood cancer patients with TET2 mutations, explained Dr. 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.
Findings
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,” said 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.”
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, said Dr. Cimmino, given that it turns up any TET2 activity normally in place.
The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
