. Vitamin C triggers faulty stem cells
in the bone marrow to mature and die instead of multiplying and causing blood
cancer, when tested in mice.
‘High-dose vitamin C treatment induced stem cells to mature, and also suppressed the growth of leukemia cancer stem cells.’
"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:
- 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
