Zebrafish may point the way toward genes responsible for T cell leukemia

Scientists hunting for genes responsible for acute lymphoblastic leukemia have a new compass: a system that uses powerful genetic techniques in a zebrafish model. Researchers report they have created a zebrafish model that will help scientists pinpoint genes that accelerate or delay the spread of T cell acute lymphoblastic leukemia (ALL), a disease responsible for 400 deaths – about half of them, children – in the United States each year. The model may also provide a faster, more direct way of testing novel drugs against the disease.From the Dana-Farber Cancer Institute:Genetically modified zebrafish may point the way toward genes responsible for T cell leukemia, aid in drug development

Scientists hunting for genes responsible for acute lymphoblastic leukemia have a new compass: a system that uses powerful genetic techniques in a zebrafish model.

In the Feb. 7 issue of the journal Science, researchers at Dana-Farber Cancer Institute, Children’s Hospital Boston, Brigham and Women’s Hospital, and other institutions report they have created a zebrafish model that will help scientists pinpoint genes that accelerate or delay the spread of T cell acute lymphoblastic leukemia (ALL), a disease responsible for 400 deaths – about half of them, children – in the United States each year. The model may also provide a faster, more direct way of testing novel drugs against the disease.

“The zebrafish, in many ways, serves as a good model of human cancers,” says the study’s senior author, Thomas Look, MD, of Dana-Farber. “Its genome is thought to contain about 30,000 genes, roughly the same number as in the human genome, and many genes correspond closely between the two species. Moreover, the fish develop an array of tumors similar to those in humans, but it has been difficult to find a way of using them as a model of human cancer. In this study, we’ve succeeded in generating T cell leukemia in the fish by causing a key cancer gene to become overactive.”

The researchers developed the zebrafish model by fusing the gene Myc, which plays an important role in human leukemia and lymphoma, to a zebrafish gene that works exclusively in lymphoid cells – the type of cells that become diseased in leukemia. The researchers tagged the fused gene with a third gene that would cause leukemia cells to glow green under fluorescent light, enabling them to observe the cancer as it progresses through the animals’ bodies. The three-gene combo was then injected into embryonic zebrafish, causing the genes to be incorporated in all of the developing fish’s cells.

“We found that cancer developed in virtually all the fish that carried a functional Myc gene,” explains Look, who is also a professor of pediatrics at Harvard Medical School.

Researchers observed that concentrations of the fluorescent-green leukemia cells first appeared in the fish’s thymus gland (involved in the development of the immune system), spread to the nearby gills and tissue behind the eyes, then disseminated further into the skeletal muscle and abdominal organs. Because of the zebrafish’s translucent skin, the researchers could easily track the spread of the fluorescent green leukemia cells.

The creation of zebrafish genetically programmed to develop leukemia will enable researchers to screen thousands of zebrafish genes for those that, in mutated form, contribute to the disease. Although Myc is involved in the cancer process, it does not act alone. It works in concert with other genes – a so-called molecular “pathway” – to drive cancer development. The goal is to find those other abnormal genes.

From their stock of Myc-carrying zebrafish, researchers plan to create individually “mutagenized” fish, each of which lacks hundreds of functional genes. By tracking which fish develop leukemia unusually quickly or unusually slowly, investigators hope to identify mutations that promote cancer and those that deter it. That knowledge will provide researchers with new targets for drugs capable of treating or preventing the disease in people at risk for it.

The availability of Myc-implanted fish also opens the way to a new way of screening potential ALL drugs. By introducing the cancer-prone fish to a variety of potential anti-leukemia compounds and observing the effect, researchers will have an indication of which are most likely to be active against the disease.

“The development of this line of zebrafish is an important step toward the identification of genes that underlie T cell ALL and toward the discovery of agents capable of treating it,” Look says. “We’re hoping to be able to find these answers in the next few years.”

David Langenau of Dana-Farber and a graduate student at Harvard Medical School is the paper’s first author. The other authors are Adolfo Ferrando, MD, PhD, and John Kanki, PhD, of Dana-Farber; David Traver, PhD, Nikolaus Trede, MD, PhD, and Leonard Zon, MD, Children’s Hospital Boston; Jeffery Kutok, MD, PhD, and John Aster, MD, PhD, Brigham and Women’s Hospital; Shuo Lin, PhD, University of California, Los Angeles; and Ed Prochownik, MD, PhD, Children’s Hospital of Pittsburgh.

The study was funded in part by the National Institutes of Health.

Dana-Farber Cancer Institute is a principal teaching affiliate of the Harvard Medical School and is among the leading cancer research and care centers in the United States. It is a founding member of the Dana-Farber/Harvard Cancer Center (DF/HCC), designated a comprehensive cancer center by the National Cancer Institute.

Editor’s note: A series of images that show a zebrafish becoming fluorescent green as the leukemia cells spread are available by contacting Science at (202) 326-6440 or [email protected]

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