Resetting gene expression may lead to new leukemia treatment

March 7 (UPI) -- Researchers at Rockefeller University in New York have developed a new technique to reset gene expression that may lead to combination therapies to treat leukemia.

A team of researchers was able to disrupt the proteins known as histones, which regulate genes to deactivate cellular programs involved in tumor growth.

Histones provide the physical support structure for the genome and help regulate gene expression. Changes to histones through chemical modifications can turn genes on or off, then the cell interprets these chemical marks with a variety of reader proteins.

The reader proteins recognize and bind to chemically-modified histones and recruit other factors that coordinate gene activation or inhibition. This process becomes disrupted in cancer, but drugs can be used to selectively inhibit the class of reader proteins known as BET proteins to treat certain cancers.

In the new study, researchers at Rockefeller University identified a class of reader proteins with the same therapeutic potential as BET proteins.

The proteins share a structural feature called a YEATS domain, which recognizes histones modified with a type of chemical mark known as an acetyl group.

"The functional importance of this reading activity by the YEATS domain was unknown," Liling Wan, a researcher in the Laboratory of Chromatin Biology and Epigenetics at Rockefeller University, said in a press release.

For patients with leukemia, cells have genomic rearrangements that fuse the gene encoding the protein MLL with the YEATS domain proteins, including one called ENL. These rearrangements are associated with poor prognosis, especially in young patients.

"In infants, it occurs in more than 70 percent of acute lymphoid leukemia and in more than 35 percent of acute myeloid leukemia cases," Wan said.

The study showed ENL may act as an engine for tumor growth, which could be halted with a well-designed inhibitor.

Researchers found that mice transplanted with ENL-depleted leukemia cells did better than those receiving unmodified leukemia cells. The cancer cells in the mice treated with ENL-depleted leukemia did not divide as quickly and the mice survived longer.

"We look forward to the development of new drugs that can block YEATS domain function, perhaps working in concert with existing bromodomain inhibitors that are already in clinical trials," said David Allis, head of the Laboratory of Chromatin Biology and Epigenetics.

The study was published in the journal Nature.