Misread epigenetic signals play role in leukemia

A genetic mistake may lead to misinterpretation of the chemical tags that help control gene activity

Scientists have shed light on how a genetic mutation linked to acute myeloid leukemia may trigger the disease. The problem arises when cells misinterpret chemical tags called epigenetic marks on certain key genes, a new study shows.

Similar problems probably lie at the heart of other cancers and diseases and may represent a new category of diseases, researchers report online May 10 in Nature.

Cancer may result from many different triggering events. In some patients with the blood cancer, the trigger seems to be a rearrangement of small pieces of chromosome, researchers discovered last year. The rearrangement fuses parts of two proteins — NUP98 and JARID1A — together. Now, Gang Wang and David Allis of Rockefeller University in New York City and their colleagues show how the pairing of the two proteins might lead to trouble for a cell.

The mutation appears to interfere with the cell’s ability to regulate epigenetic marks, which act as volume controls, on some genes. The misunderstanding can lead to cancer.

One of the two proteins, NUP98, has already been implicated in several types of leukemia, specifically when the protein fuses with another protein. In this case, NUP98 is fused to a part of the JARID1A protein called a PHD finger that’s involved in “reading” epigenetic tags. PHD fingers help a cell interpret chemical marks on DNA-associated proteins called histones — proteins that wrap up DNA so it will fit inside a cell. Chemical tags on the tails of the histone proteins affect how tightly the DNA is wound around the proteins, which in turn influences gene activity.

JARID1A’s PHD finger reads a particular mark on the tail of histone H3. The mark is a signal to the cell’s machinery that a gene should be turned on, essentially read aloud by the molecular equivalent of a text-to-speech reader. Other types of marks designate that a passage should be read quietly or skipped entirely. 

Normally, when the PHD finger latches on to the mark, the protein erases the mark, hushing up the gene. But Wang found that when the PHD finger is fused to NUP98, the finger can still read the mark but fails to erase it.

“That’s bad news number one,” Allis says. 

Bad news number two is that the fused proteins act as a cap, preventing other molecules from erasing the “on” mark. Indeed, instead of hitting the mute button, the fused proteins recruit other gene activators, turning the volume up to 11 on some genes. The genes marked for shout-outs by the fused proteins include several from the Hox family that are important in prompting a cell to replicate itself. So instead of shutting down replication and developing into a working blood cell, a bone marrow cell with the mutation remains in an amorphous state and reproduces wildly, a hallmark of cancer.

“The cell is really confused,” Allis says. The fused proteins have “flipped everything to the opposite state.”

One day, chemotherapy drugs aimed at the PHD fingers might help a cell reinterpret the epigenetic marks correctly, Allis suggests.

Scientists don’t yet know whether this misinterpretation is a common cause of cancer or other diseases, but Yang Shi, a molecular biologist at Harvard Medical School in Boston, says it is likely that mistakes in reading epigenetic marks could have dire consequences.

“Cells have dedicated a lot of resources to developing this network of proteins that are dedicated to reading and interpreting histone modifications,” Shi says. “These recognition modules are going to be very important in gene regulation,” and disease.

Tina Hesman Saey is the senior staff writer and reports on molecular biology. She has a Ph.D. in molecular genetics from Washington University in St. Louis and a master’s degree in science journalism from Boston University.

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