Image by Lance Liotta
AML cells
Researchers have described a molecular mechanism that could help explain the link between low vitamin C (ascorbate) levels and acute myeloid leukemia (AML).
The team found that mice with low levels of ascorbate in their blood experience a notable increase in hematopoietic stem cell (HSC) frequency and function.
This, in turn, accelerates AML development, partly by inhibiting the tumor suppressor Tet2.
Sean Morrison, PhD, of the University of Texas Southwestern Medical Center in Dallas, and his colleagues reported these findings in Nature.
“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,” Dr Morrison said. “Our research provides part of the explanation, at least for the blood-forming system.”
Dr Morrison and his colleagues developed a technique for analyzing the metabolic profiles of rare cell populations and used it to compare HSCs to restricted hematopoietic progenitors.
The researchers found that each hematopoietic cell type had a “distinct metabolic signature,” and both human and mouse HSCs had “unusually high” levels of ascorbate, which decreased as the cells differentiated.
To determine if ascorbate is important for HSC function, the team studied mice that lacked gulonolactone oxidase (Gulo), an enzyme mice use to synthesize their own ascorbate. Loss of the enzyme requires Gulo-deficient mice to obtain ascorbate exclusively through their diet like humans do.
So when the researchers fed the mice a standard diet, which contains little ascorbate, the animals’ ascorbate levels were depleted.
The team expected ascorbate depletion might lead to loss of HSC function, but they found the opposite was true. HSCs actually gained function, and this increased the incidence of AML in the mice.
This increase is partly tied to how ascorbate affects Tet2. The researchers found that ascorbate depletion can limit Tet2 function in tissues in a way that increases the risk of AML.
In addition, ascorbate depletion cooperated with Flt3 internal tandem duplication mutations to accelerate leukemogenesis. But the researchers were able to suppress leukemogenesis by feeding animals higher levels of ascorbate.
“Stem cells use ascorbate to regulate the abundance of certain chemical modifications on DNA, which are part of the epigenome,” said study author Michalis Agathocleous, PhD, of the University of Texas Southwestern Medical Center.
“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.”
The researchers said further studies are needed to better understand the potential clinical implications of these findings.
However, the findings may have implications for older patients with clonal hematopoiesis. This condition increases a person’s risk of developing leukemia, but it is not well understood why certain patients develop leukemia and others do not. The results of 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,” Dr Morrison said. “Our results suggest patients with clonal hematopoiesis and a TET2 mutation should be particularly careful to get 100% of their daily vitamin C requirement. 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.”
