Process triggered by some anti-cancer drugs causes tumors in mice, study finds

which can turn genes on or off, attach to the bases of an organisms DNA.

In many cancer cells, too few methyl molecules attach to DNA, a condition scientists call hypomethylation. But until now, scientists didnt know which came first the cancer or the hypomethylation. Franois Gaudet, a graduate student in Jaenischs lab, spent several years developing mice transgenically designed to be hypomethylated.

It was a shot in the dark to see whether we could generate animals that could actually survive, and at the same time be hypomethylated, said Gaudet.

Gaudets mice expressed only about 10 percent of normal levels of methyltransferase, the enzyme that maintains normal levels of methylation. About 80 percent of the mice developed an aggressive form of leukemia, a tumor that is derived from the thymus. Whats more, the cancer cells detected were the same throughout a tumor, suggesting that the tumor grew from a single hypomethylated abnormal cell. And, in fact, a gene called c-myc, known to be associated with tumor formation, was seen to be overly active in the cells.

Gaudet found that the tumors had an extra copy of chromosome 15, the same chromosome where the c-myc gene is found. This explains higher activity of c-myc, he added. Chromosome aberrations such as trisomies three copies of a chromosome instead of two or chromosome loss are hallmarks of human tumors, particularly leukemia.

Knowing that hypomethylation can cause cancer raises questions about ongoing clinical trials, Gaudet said. The induction of hypomethylation might treat cancer in some tissues but may induce cancer in other tissues, Gaudet said. It is important therefore to test the effect of hypomethylation on cancer in different tissues.

Extending Gaudets work, Amir Eden, a postdoctoral fellow in Jaenischs lab, found that even mice engineered to develop tumors did so earlier when hypomethylated. Edens mice had mutations in genes that normally suppress tumor

Contact: Kelli Whitlock or Melissa Withers
Whitehead Institute for Biomedical Research

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