Cellular clocks control some childhood cancers

In a recent study conducted at Hopkins, researchers found that childhood cancers are linked to an internal cellular clock which regulates the timing of genetic exchange in dividing immune cells.

During immune cell division, bits of DNA randomly recombine to form brand new immune cells. The recombined DNA can encode special proteins that can attack an enormous variety of potential pathogens and tumor cells.

The newly formed cells are equipped with a different genome than that of their parents’ cells; this allows them to diversify their attack and increase their capacity to protect the body. Known as V(D)J recombination, the mechanism combines Variable, Diverse, and Joining gene segments to ensure versatile immune system function.

The study, published in Immunity on Feb. 24th, shows that V(D)J recombination is dependent on a molecular cellular clock, which regulates the timing of DNA recombination during the cell cycle.

“We expose ourselves to the real possibility of cancer every time we make a new immune cell,” said Stephen Desiderio, director of the Institute for Cell Engineering Immunology Program at the Hopkins School of Medicine in a press release. “One of the many safeguards in place to ensure that bad things don’t happen often now appears to be a cellular clock that times these potentially dangerous events and regulates them.”

In the study, Desiderio and his team separated V(D)J recombination from the cellular clock in mice; this caused the development of abnormal chromosomes and cancer cells.

The research team was able to genetically manipulate mice chromosomes so that a protein called Rag2 would remain active once the chromosomes were isolated. Rag2 is responsible for cutting DNA so that it can be reassembled in the new cells.

Under normal conditions, Rag2 is only active during V(D)J recombination and is cleared away by a regulatory protein before the next phase of DNA replication.

When it was left active throughout all phases of the cell cycle, Rag2 cut the wrong genetic material at the wrong time, creating abnormal chromosomes.

“The ability to rearrange genetic material oscillates, and that oscillation corresponds to the cell cycle,” Desiderio said.

romosome “painting,” the researchers were able to see the various fragments of DNA incorrectly recombine. They found that the DNA fragments were unable to properly attach and that their host immune cells died at a faster rate than normal cells.

The team also noticed that cancer-causing genes, which are not typically involved in V(D)J recombination, had recombined with the DNA fragments.

“The DNA sequences at those abnormal junctures we saw in mouse tumor cells mimicked the kind that were seen in a previous study of cells taken from children with lymphoid cancers,” Desiderio said.

“This could provide an explanation about why those junctures occurred in those children and why we see abnormal chromosomes.”

This new information about V(D)J recombination being linked to a cellular clock can potentially explain the cause of some tumors in children.

“Knowing the underlying mutations that make it more likely for a child to get these abnormalities could mean, at the very least, that we might be able to identify those children and watch more closely,” Desiderio said. “And perhaps in the future, the knowledge might even instigate new therapy.”