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Johns Hopkins Scientists Tie Cell Cycle “Clock” To Childhood Cancers - 02/24/2011

Johns Hopkins Scientists Tie Cell Cycle “Clock” To Childhood Cancers

Release Date: February 24, 2011

Abnormal chromosomes have long been detected in children with leukemias and lymphomas, and now, research by Johns Hopkins scientists has linked such abnormalities with a molecular clock that controls the timing of a high-stakes genetic exchange inside dividing immune system cells.

When an immune cell divides, its DNA breaks into snippets that pair up anew with all the dynamism and daring of a troupe of trapeze artists. The Hopkins team showed how this cellular act — the crash of which can result in cancer — depends as much on precision timing as any circus performance.

“We expose ourselves to the real possibility of cancer every time we make a new immune cell,” says Stephen Desiderio, M.D., Ph.D., director of the Institute for Cell Engineering Immunology Program at the Johns Hopkins University School of Medicine. “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.”

The Johns Hopkins study, reported February 24 online in Immunity, reveals that the swap act known as V(D)J recombination is tethered to a cellular clock that determines when DNA will be cleaved and its segments reshuffled inside dividing  immune cells. When the team uncoupled recombination from the clock in immune cells from mice, abnormal chromosomes and cancer cells resulted. 

V(D)J recombination enables an immune cells’ offspring to confer all-new and different protection than the parent cell from which they derived, ultimately allowing for diversity in an immune system that must recognize and stave off  a huge variety of invaders. About ten million such recombination events will occur while you read this, making potential mismatches of genetic bits a threat that could generate abnormal rearrangements in growth control genes. Such rearrangements may wreak havoc in the immune system instead of bolstering it.

For their study, Desiderio and his team first isolated chromosomes from the tumor cells of mice that had been genetically manipulated so that the molecular knife that chops up DNA inside of immune system cells — a protein called Rag2 — would stay active all the time. The manipulation essentially uncoupled the V(D)J recombination from the cell cycle clock. Instead of being destroyed by a protector protein, Rag2 continued to cut DNA into pieces during all phases of the cell cycle. 

Rag2 normally is available only at one discrete window of time during the cell cycle when V(D)J recombination occurs. Rag2 promptly is disabled and cleared away from the cell by a regulatory protein acting like the gears of the cell cycle clock and guiding proper DNA reassembly. All of this occurs before the cell cycle progresses into its next phase when DNA replicates.

Desiderio says their work shows that if not disabled prior to DNA replication, Rag2 could chop the wrong genetic material at the wrong places at the wrong time. Strange bits could join promiscuously in odd ways, causing abnormal chromosomes to occur.

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

By using a chromosome “painting” technique to render the severed pieces of genes in different colors, the team could see under a microscope that cells in the developing immune system died at a much greater rate than normal, presumably because the broken bits of DNA weren’t properly recombining. In addition, they noticed that many of the combination reactions that did occur had faulty “seams” where the gene segments had joined. And they revealed that bits of genes not normally involved in the V(D)J recombination process — most notably, cancer-causing genes — had joined in the swapping act.

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

In a final experiment, the team crossed two mutant mouse strains: one in which they had mutated the Rag2 gene in order to unfasten the cell cycle clock from V(D)J recombination, and one that lacked a gene regulating cell death. These animals, lacking both Rag2 and the ability for aberrant cells to die as they normally would, developed florid tumors.

“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 says. “And perhaps in the future, the knowledge might even instigate new therapy.”

Authors of the paper, in addition to Stephen Desiderio, are Li Zhang and Taylor Reynolds, both of Johns Hopkins. Also, Xiaochuan Shan of the University of Pennsylvania.

This research was supported by a grant from the National Cancer Institute and a gift to the Institute for Cell Engineering.

For the Media

Media Contacts:
Audrey Huang; 410-614-5105; audrey@jhmi.edu
Vanessa McMains; 410-502-9410; vmcmain1@jhmi.edu

 
 
 
 
 
 

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