"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 Genetic Code Reduce Tet2 Function

Ten percent of patients with acute myeloid leukemia (AML) have changes in the genetic code that reduce TET2 function. The same can also be noted in 30% of those with myelodysplastic syndrome, and in nearly 50% of patients with chronic myelomonocytic leukemia.

Abnormal stem cells multiply in the bone marrow and cause cancers that cause anemia, infection risk, and bleeding. These abnormalities interfere with blood cell production. Each year about 42,500 new patients may develop TET2 mutations, including some with lymphomas and solid tumors.

Certain genetic changes are known to reduce the ability of an enzyme called TET2 to encourage stem cells to become mature blood cells that 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.

Genetic Reason Behind Blood Cancer

Cytosine, one of the four nucleic acids that comprise the DNA code in genes and its relationship with TET2 enzyme exhibit the effect. Every cell has different instructions to turn on only those genes that are needed.

DNA methylation, the attachment of a methyl molecule to cytosine bases shuts down the action of a gene containing them. The attachment and removal of methyl groups tune the expression in stem cells to mature, specialize and multiply to become muscle, bone, nerve, or other cell types.

This process starts when the body begins to form in the womb but the bone marrow harbors stem cells on hand to replace cells up until adulthood.

Tet methylcytosine dioxygenase 2 (TET2), the enzyme in focus in the study enables oxidation of methyl groups that is needed for them to be removed from cytosines. This demethylation directs stem cells to mature and self-destruct.

Mechanism Behind The Vitamin C Effect

Previous research has shown that vitamin C could stimulate the activity of TET2 and its relatives TET1 and TET3. In TET2-mutant blood diseases, only one of the two copies of the TET2 gene in each stem cell is usually affected. High doses of vitamin C might reverse the effects of TET2 deficiency by turning up the action of the remaining functional gene.

The research team genetically engineered mice to determine the effect of mutations that reduce TET2 function in abnormal stem cells.

Turning off TET2 in mice caused abnormal stem cell behavior similar to those in humans. But when TET2 expression was restored, these changes were reversed.

Intravenous dose of vitamin C did the same thing as restoring TET2 function genetically. Vitamin C induced stem cells to mature, and also suppressed the growth of leukemia cancer stem cells by promoting DNA demethylation.

"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.

The combination of vitamin C with a PARP inhibitor, a drug type known to cause cancer cell death had an enhanced effect on leukemia stem cells. PARP inhibitors are already approved for treating certain patients with ovarian cancer. The drug blocks the repair of DNA damage.

Corresponding author Iannis Aifantis said, "Our team is working to systematically identify genetic changes that contribute to risk for leukemia in significant groups of patients. This study adds the targeting of abnormal TET2-driven DNA demethylation to our list of potential new treatment approaches."

Reference:

1. Benjamin G. Neel et al.,Restoration of TET2 Function Blocks Aberrant Self-Renewal and Leukemia Progression. Cell DOI:http://dx.doi.org/10.1016/j.cell.2017.07.032

Source: Medindia