Posted on Aug 22, 2017, 6 a.m.
Vitamin C may prompt faulty stem cells in bone marrow to die off, rather than multiplying to spur blood cancers.
A new study has found that vitamin C may communicate to faulty stem cells within bone marrow that they should mature and perish in a normal manner rather than multiplying to spur blood cancers. This is the insight gleaned from a study spearheaded by NYU Langone Health Perlmutter Cancer Center researchers. Study details were recently published in Cell.
About the Findings
The authors of the study state specific genetic alterations are known to decrease the ability of an enzyme referred to as tet methylcytosine dioxygenase 2 (TET2) to promote stem cell maturation and death in patients who have specific types of leukemia. They determined vitamin C activates TET2 functionality in mice designed to lack the enzyme. It is possible that vitamin C will prove to be a safe and effective treatment for diseases spurred by leukemia stem cells deficient in TET2. It is likely that vitamin C will be used in combination with other targeted therapies.
The researchers used genetically altered mice in which TET2 was turned off. These mice endured abnormal stem cell activity. Such changes were reversed when a genetic trick restored TET2 expression. Providing high doses of vitamin C functioned similarly to restoring TET2 functionality on a genetic level. Vitamin C's promotion of DNA demethylation caused stem cells to mature and limited the advancement of leukemia cancer stem cells from humans that were implanted in mice. Vitamin C treatment affected leukemic stem cells similar to damaged DNA. Vitamin C was used in combination with a PARP inhibitor to produce an enhanced effect on such stem cells, sending them from self-renewal to maturity and subsequent death.
TET2 and Cancer
Alterations in the genetic code that decrease TET2 functionality are found in 10% of those who have acute myeloid leukemia (AML). About one-third of patients with a form of preleukemia known as myelodysplastic syndrome and upwards of half of those with chronic myelomonocytic leukemia have such genetic code mutations. These cancers spur anemia, bleeding and infection risk as abnormal stem cells multiply within bone marrow until they block the production of blood cells. Recent tests show about 2.5% of cancer patients living in the United States might develop TET2 alterations. This includes some patients with solid tumors and lymphomas.
About Cell Death Switch
The results of the study center on the relationship between cytosine and TET2. Cytosine is one of the several letters of nucleic acid that make up genes' DNA code. Each cell type has the same genes yet each receives unique instructions to turn on only those required in a specific cellular context. Examples of such epigenetic mechanisms include DNA methylation. This is an attachment of a diminutive molecule to cytosine bases to put a halt to the action of a gene containing them. Gene expression within stem cells is fine-tuned when methyl groups are attached and removed. Stem cell expressions can then mature and multiply to form muscle, nerve, bone and other types of cells. The bone marrow holds stem cell pools as adulthood is reached until they can become replacement cells. In patients with leukemia, signals that typically tell blood stem cells to mature end up malfunctioning. This allows for endless multiplication and a self-renewing rather than the generation of regular white blood cells required to combat infection.
TET2 empowers an alteration in the molecular structure of methyl groups required for their removal from cytosines. Such demethylation activates genes that direct stem cells to mature and commence a countdown to self-destruction as a component of regular turnover. This functions as a means of combating cancer yet it is disrupted in blood cancer patients who have TET2 mutations.
Luisa Cimmino, Igor Dolgalev, Yubao Wang, Akihide Yoshimi, Gaëlle H. Martin, Jingjing Wang, Victor Ng, Bo Xia, Matthew T. Witkowski, Marisa Mitchell-Flack, Isabella Grillo, Sofia Bakogianni, Delphine Ndiaye-Lobry, Miguel Torres Martín, Maria Guillamot, Robert S. Banh, Mingjiang Xu, Maria E. Figueroa, Ross A. Dickins, Omar Abdel-Wahab, Christopher Y. Park, Aristotelis Tsirigos, Benjamin G. Neel, Iannis Aifantis. Restoration of TET2 Function Blocks Aberrant Self-Renewal and Leukemia Progression. Cell, 2017; DOI: 10.1016/j.cell.2017.07.032http://nyulangone.org/press-releases/vitamin-c-may-encourage-blood-cancer-stem-cells-to-die