This new genetic switch, reported in the March 19 issue of the Proceedings of the National Academy of Sciences, turns on a program to destroy certain leukemic cells and possibly other tumor cells. It is activated by treatment with retinoic acid, a vitamin A derivative used in cancer therapy and prevention.
Finding a mechanism that sets a cell death program in motion paves the way for developing new cancer-killing drugs, according to Ethan Dmitrovsky, professor and chair of pharmacology and toxicology. He headed the research team that included Sutisak Kitareewan, Ian Pitha-Rowe, Sarah Freemantle and David Sekula.
Retinoids are natural or synthetic compounds derived from vitamin A. The retinoid all-trans retinoic acid (RA) causes remissions in acute promyelocytic leukemia (APL), a rare, but lethal leukemia. This leukemia is marked by an unusual genetic defect that rearranges the receptor for RA. A hallmark of this retinoid response is the degradation of the abnormal receptor that causes this disease.
Studying the RA pathway, the DMS team found a target gene that appears to mimic the drug action, degrade the abnormal receptor and induce cell death. When introduced into leukemic cells, this gene, called UBE1L, reproduced key aspects of retinoic acid response and caused the death of leukemic cells.
"This is exciting because we have identified a potential pharmacological target that signals a death program in leukemia and perhaps other cancer cells as well," says first author Kitareewan.
Dmitrovsky's team collaborated with Dartmouth researchers Christopher Lowrey, associate professor of medicine and of pharmacology and toxicology, and Michael Nemeth, as well as Todd Golub of Harvard. Dmitrovsky and Lowrey are physicians of Dartmouth's Norris Cotton Cancer Center. Their work was supported by the National Institutes of Health.
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Proceedings of the National Academy of Sciences