Researchers have halted the progression of leukemia in mice by restoring the enzyme TET2 in hematopoietic stem cells, either by reestablishing its gene expression in transgenic mice or by promoting the protein’s function with high doses of vitamin C, The Scientist says.
In their study, published on Thursday, August 17 in Cell, the authors found that the absence of this protein continuously drives a pre-leukemic state in hematopoietic stem cells, while its renewed presence can arrest leukemia progression. Notably, they also showed that boosting TET2’s enzymatic activity with vitamin C can make up for diminished amounts of the protein in deficient mice.
This is a “very important study that will definitely have a very lasting impact on the field,” says Ulrich Steidl of the Albert Einstein College of Medicine who was not involved in the study. It will likely “inspire a lot of scientists and translational investigators to think about similar strategies and to go after these pre-leukemic stem cells, which, in my opinion will be critical if we’re ultimately aiming for a cure.”
The authors previously demonstrated that a lack of TET2, often one the first mutations leukemia patients acquire, promotes leukemia in mice. TET2 is important for driving DNA demethylation, and leukemia patients with TET2 mutations exhibit hypermethylated DNA, in addition to accumulating hematopoietic stem cells that don’t mature like they’re supposed to—a hallmark of the disease.
“Without that wave of DNA demethylation to allow the [hematopoietic stem] cells to differentiate, they get stuck in a progenitor state,” explains lead author Luisa Cimmino, an assistant professor of pathology at New York University Langone Health. “So, you have this accumulation of this proliferating population of hypermethylated cells that aren’t getting the signal to fully differentiate.”
To further probe TET2’s role in fostering the cancer, they engineered mice so that TET2 gene expression could be reversibly knocked down or restored using RNA interference (RNAi). The researchers then transplanted bone marrow from the transgenic mice into genetically normal, disease-free counterparts.
Symptoms of a leukemia-like state progressed in mice transplanted with TET2 knock down cells. But when the researchers restored TET2 gene expression, it blocked disease progression.
Vitamin C works to reduce iron into a state that can be reused by TET2 to perform key steps in DNA demethylation, explains senior author Benjamin Neel, director of the Perlmutter Cancer Center at NYU Langone Health.
“For the TET enzyme to be catalytically active, it needs to have iron readily available,” he says. If there wasn’t a way to convert the iron back into a useable state, “each [TET2] enzyme would only be able to do one reaction, then it would be dead.”