A signaling system involved in many forms of leukemia and lymphoma is more powerful than scientists have thought, exerting control over our genes by affecting whole swaths of chromosomes in global fashion, according to a paper in the September issue of Nature Genetics and appearing online August 6.
While the research involving a cellular signaling system known as JAK/STAT focused on complex questions involving the roots of cancer, the answers the researchers got came very simply and clearly -- in red and white. By looking at the eye color of a variety of mutant flies, the team at the University of Rochester Medical Center made a surprising finding about a known cancer gene that meshes nicely with current trends in cancer drug research.
Instead of developing drugs that target a single gene or protein, many companies are taking aim at the way whole sets of genes are packaged in an attempt to turn on or off several genes at a time. It's part of a field known as "epigenetics": Now that the sequence of chemical bases that make up our genes is largely known, scientists are turning more attention to broader mechanisms of how the body controls those genes, turning them on and off as needed.
It's a crucial issue for diseases like cancer, where many genes are turned on or off when or where they shouldn't be, causing cells to grow out of control. A system similar to JAK/STAT in humans, for instance, is vital for normal health, helping us fight disease and grow new blood cells, but when its signals run amok, those people are much more likely to get any one of several types of leukemia or lymphoma.
To learn more about how JAK/STAT works, a team led by Willis Li, Ph.D., assistant professor in the Department of Biomedical Genetics, devised a complex experiment involving fruit flies. Researchers created flies with normal amounts of the signaling system and compared them to mutant flies with increased or decreased JAK/STAT signaling. They moved the location of the "red-eye reporter gene" around, sometimes inserting it into a "quiet" stretch of DNA, sometimes putting it into an active area, and sometimes inserting it near the border between the two regions. The team used the gene that controls eye color to check whether a given stretch of DNA was on or not. If the fly's eyes were red, the gene was turned on; if the fly's eyes were white, the gene was turned off.
In flies with normal amounts of JAK/STAT, the eye color was predictable based on where the gene was inserted -- the gene was silent when expected, producing flies with white eyes, and active when expected, producing flies with red eyes. But in flies with increased JAK/STAT signaling, similar to what occurs in many leukemia patients, Li's team unexpectedly found that some flies that should have had white eyes had red eyes instead. The red-eye gene was sometimes active when it should have been silenced.
The research shows that JAK/STAT was able to open up the previously silent part of the genome, somehow turning on the red-eye gene by changing the gene's packaging. Genes that were previously turned off or silenced were turned on once JAK/STAT changed the genetic packaging. The team's results suggest that the pathway's ability to cause cancer is largely due to this ability; cancer-causing genes that are normally turned off become turned on once high levels of JAK/STAT open up that stretch of DNA.
Such work zeroes in on the way the body compacts a slew of genetic information into our cells while keeping the fragile DNA strands safe. Our DNA contains tens of thousands of genes along the seven feet of DNA that is spooled up very tightly around proteins called histones in the nucleus of nearly every cell in our bodies. The whole structure, called chromatin, looks much like a narrow thread wound tightly around a stack of tuna cans. While there are genes aplenty in every cell, not all our DNA is equally accessible to the cellular machinery that turns genes on or off, and only some genes are active in any given cell at any one time.
How our body regulates access to our genes and makes stretches of DNA available is a booming area of study for scientists who study "chromatin remodeling." When a gene is spooled up tightly, it's as if it has been confined by a straightjacket -- it's unavailable or "silenced" and can't be turned on. To become available, a gene must be part of a stretch of DNA that relaxes and loosens up, becoming accessible to a variety of molecular signals.
JAK/STAT signaling is one of the first molecular mechanisms to be identified as controlling chromatin remodeling. Its work resembles that of a criminal mastermind busting a hoodlum out of jail so he can make more mischief. Behind bars, effectively inactive and silenced, the hoodlum -- in this case, a cancer-causing gene causing cells to grow out of control -- is not dangerous. When JAK/STAT frees the scofflaw, it's free to then meet up with its molecular buddies and wreak havoc on the body.
It was just last year that a team of scientists in Germany showed in an article in Nature that tightly wound DNA that is unavailable, known as heterochromatin, can suppress tumor growth by keeping genes that tell cells to grow turned off. Li's paper goes one step further, identifying JAK/STAT, a known cancer-causing pathway in people, as one mechanism that has the ability to turn on sets of genes that have been silenced in this way.
Scientists have thought that JAK/STAT works by directly turning on genes that make tumor cells grow, fitting a more traditional view of how genes are turned on and off. The new findings make the molecule something of a super-oncogene with more global control than scientists had considered. The signaling system thus seems unique because it can both cause cancer directly, or knock out genetic mechanisms that suppress cancer.
"A molecule that is both an oncogene and that also antagonizes a tumor suppressor mechanism is pretty powerful," Li said. "Most genes involved in cancer do one or the other, not both."
The work fits in squarely with pharmaceutical research on experimental drugs known as HDAC (histone deacetylase) inhibitors, which affect chromatin structure and play a role in turning on or off whole swaths of DNA. Such drugs are under investigation for leukemia and several other diseases. Based on Li's work, using a drug to target the JAK/STAT pathway may offer a new strategy for altering chromatin structure, much like HDAC inhibitors do.
"We hope that others will take what we have learned from fruit flies and apply the findings to people," said Li. "If this phenomenon occurs in people as well as flies, which is likely, it could form the basis for new treatments for people with leukemia and lymphoma."
The studies conducted in fruit flies by Li, who aims to understand the extraordinarily complex cell signaling that brings about cancer in people, would be impossible to do directly in humans. Turning to fruit flies lets Li and other fruit fly geneticists speed up cancer research by stripping down the complexity of the organism, discovering the major themes, and then using those as a guide when studying people directly.
Li's laboratory has just received $1.7 million in funding for the next four years of research. The National Institute of General Medical Sciences is providing approximately $1 million and the American Cancer Society is providing $720,000 to enable Li to continue his studies of the cell signaling that causes cancer.
Li's colleagues on the Nature Genetics study, which was funded by the National Institutes of Health, include graduate students Song Shi and Fan Xia; post-doctoral researchers Jinghong Li and Long Le; and former undergraduate technician Healani Calhoun.
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