Reprogramming stem cells may prevent cancer after radiation

Radiation makes a stem cell lose its stem-ness, making stem cells damaged by radiation differentiate into other cells that can no longer survive forever. This effect makes sense as damaged stem cells would produce damaged cells, which is an unwanted result (Stem Cells. 2014; doi:10.1002/stem.1936).

The study also shows that this same safeguard of programmed mediocrity that weeds out stem cells damaged by radiation allows blood cancers to grow in cases when the full body is irradiated. By reprogramming this safeguard, we may be able to prevent cancer in the aftermath of full body radiation.

“The body didn't evolve to deal with leaking nuclear reactors and CT scans. It evolved to deal with only a few cells at a time receiving dangerous doses of radiation or other insults to their DNA,” said James DeGregori, PhD, investigator at the University of Colorado Cancer Center in Denver, professor of Biochemistry and Molecular Genetics at the CU School of Medicine, and the paper's senior author.

DeGregori, doctoral student Courtney Fleenor, and colleagues explored the effects of full body radiation on the blood stem cells of mice. In this case, radiation increased the probability that cells in the hematopoietic stem cell (HSC) system would differentiate. Only, while most followed this instruction, a few did not.

Stem cells with a very specific mutation were able to disobey the instruction to differentiate and retain their stem-ness. Genetic inhibition of the gene C/EBPA allowed a few stem cells to keep the ability to act as stem cells. With competition from other, healthy stem cells removed, the stem cells with reduced C/EBPA were able to dominate the blood cell production system. In this way, the blood system transitioned from C/EBPA+ cells to primarily C/EBPA– cells.

Mutations and other genetic alterations resulting in inhibition of the C/EBPA gene are associated with acute myeloid leukemia in humans. Thus, it is not mutations caused by radiation but a blood system reengineered by faulty stem cells that creates cancer risk in people who have experienced radiation.

“It's about evolution driven by natural selection,” DeGregori said. “In a healthy blood system, healthy stem cells out-compete stem cells that happen to have the C/EBPA mutation. But when radiation reduces the heath and robustness (what we call fitness) of the stem cell population, the mutated cells that have been there all along are suddenly given the opportunity to take over.”

If in a situation in which he was likely to be exposed to full-body radiation, DeGregori would freeze a sample of his own HSCs. An infusion of healthy HSCs after radiation exposure would likely allow the healthy blood system to out-compete the radiation-exposed HSC and even HSCs with cancer-causing mutations, he explained.

“But there's also hope that in the future, we could offer drugs that would restore the fitness of stem cells left over after radiation.”

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