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Transgenic zebra fish with green fluorescent blood cells have helped University of Utah cancer researchers identify genetic signatures that may lead to improved treatments for children patients with leukemia.
Findings published this week could allow doctors to predict how aggressive a case will be, enabling them to limit the use of toxic chemotherapy drugs while still curing the child. Leukemia is a spectrum of blood disorders that cause a dangerous proliferation of white blood cells that have not matured.
The researchers at the U.'s Huntsman Cancer Institute targeted a type called T-cell acute lymphocytic leukemia, or T-ALL, which most commonly occurs in children. This form represents about 15 to 20 of all lymphocytic cases — 400 to 500 new cases a year in the U.S., according to co-senior author Nikolaus Trede. Current medical practices can cure 80 percent of these patients, but the side effects from the drugs can be devastating.
"They can range from weakened bones to intellectual challenges. Growth can be stunted; patients can have heart problems. We follow them long term, even for life," said Trede, an associate professor of pediatrics. "We are trying to improve the quality of life for those that are cured, to give them as little chemotherapy as possible, and improve the survival rates for the 20 percent that we cannot cure."
To explore ways to better assess patients' prognoses, Trede looked to zebra fish, which can contract T-ALL leukemia. A small freshwater tropical fish, zebra fish have horizontal blue stripes and are commonly sold for home aquariums, but they are also a boon to science as a model organism.
The U. breeds them by the thousands for use in biomedical research because they are easier to experiment with than mice.
By implanting a gene that makes the fish's T-cells florescent green, researchers can determine the severity of the disease in a particular fish, then hunt for genetic signatures in the cancer cells. Trede's study, published this week in the journal Oncogene, identified these signatures.
"One of the genes identified in the study had not previously been recognized as important in T-ALL," said co-senior author Kimble Frazer, an assistant professor of pediatrics who works in the Trede Lab. "Another gene, associated with patients whose outcomes were least favorable, has not received enough research attention to even have an official name. It only has an 'address' that tells its location on a specific chromosome."
To zero in one these genes, the researchers first created a particularly aggressive form of T-ALL in the zebrafish through a process called serial transplantation. Over the course of eight rounds of transplantation, they implanted diseased cells in the fish, which amplified its severity with each generation.
While they identified genetic signatures that are characteristic of the most aggressive type of the disease, more research is needed to understand them more fully and validate these results, the researchers said.
"Some of the genes are drivers and some are the passengers that go along for the ride but aren't important. You don't know which they are," Trede said.
Ultimately, these findings could be used to develop a test for human leukemia patients, where a bone marrow biopsy can be scanned for these genetic markers associated with a more aggressive T-ALL. Those with a less-aggressive variety could be treated with lower does of chemotherapy.
"It could be applied to other cancers," Trede said.
Authors include U. medical student Lynnie Rudner, and researchers from Brigham and Women's Hospital in Boston; University of Texas at Brownsville, the Dana-Farber Cancer Institute; Children's Hospital Boston; and St. Jude Children's Research Hospital in Memphis, Tenn. Support came from the U., the Huntsman Cancer Foundation, the National Institutes of Health and the American Medical Association.
Zebrafish
This freshwater tropical fish, a common tenant in aquariums, is used in biomedical research as a "model organism." Using these horizontally striped fish, U. researchers have identified genetic signatures associated with high-risk cases of leukemia.