Dana-Farber Cancer Institute scientists have discovered an enzyme they say accounts for a cancer-causing protein's Jekyll-and-Hyde personality. Normally, the protein regulates when and how body parts develop, but when mutated, it triggers a rare, often-lethal infant leukemia called mixed lineage leukemia.
The newly identified protease enzyme, Taspase1, plays a key role in the MLL protein's dual-personality. (A protease enzyme cuts protein molecules into smaller pieces). Blocking Taspase1, the researchers say, might provide a novel way to shut down runaway production of cancer cells. The findings are reported in the Oct. 31 issue of Cell.
"These findings demonstrate that a simple protease enzyme is required for the effects of this gene (MLL) and suggests that protease inhibitors, which have been effective with relatively few side effects in other diseases, could be a reasonable way to treat cancer," says Stanley Korsmeyer, MD, senior author of the paper.
Mixed lineage leukemia strikes fewer than 100 babies every year in the United States, but it is typically fatal in 60 percent. It is caused by damage to the MLL gene, which then makes a mutant MLL protein.
James Hsieh, MD, PhD, and Emily Cheng, PhD, are the paper's first and second authors, respectively. Both are members of Korsmeyer's laboratory.
Hsieh, Cheng and their colleagues found that in its normal state, the MLL protein switches on and regulates a special set of genes known as HOX genes. This gene set is the master controller of the development of the body in embryonic life according to a predetermined plan. The researchers now have shown that MLL cannot switch on the HOX genes without the newly discovered Taspase1 enzyme, whose task is to cut the full MLL protein into two smaller, active pieces. If HOX genes are revved up too high, blood cells are overproduced, and the patient develops leukemia.
The Dana-Farber scientists say that enzymes such as Taspase1 can make good targets for cancer drugs and they can be inhibited with oral, relatively non-toxic compounds. Thus, a drug that blocks Taspase1 might shut down the runaway proliferation of blood cells that causes the leukemia – and might work in other cancers as well.
"We'd be very interested in making an inhibitor to Taspase1, which could knock the HOX genes out of action, and test whether cancers are addicted to their HOX genes," said Korsmeyer, who is the Sidney Farber Professor of Pathology at Harvard Medical School and a Howard Hughes Medical Institute investigator.
Gary Gilliland, MD, PhD, a leukemia specialist at Dana-Farber and Brigham and Women's Hospital, commented on the paper in an accompanying editorial. Further research to follow up this new lead, he wrote, "should provide further insight into the potential therapeutic value of Taspase inhibitors in treatment of leukemia associated with MLL gene rearrangements."
The research was supported in part by grants from the National Institutes of Health.
Dana-Farber Cancer Institute is a principal teaching affiliate of the Harvard Medical School and is among the leading cancer research and care centers in the United States. It is a founding member of the Dana-Farber/Harvard Cancer Center (DF/HCC), designated a comprehensive cancer center by the National Cancer Institute.
Taspase1: A Threonine Aspartase Required for Cleavage of MLL and Proper HOX Gene Expression
James J.-D. Hsieh, Emily H.-Y. Cheng, and Stanley J. Korsmeyer
Cell, Vol 115, 293-303, 31 October 2003
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