Researchers close in on cancer

Yale researchers have crossed continental lines to zero in on a cause of leukemia.

A joint study by the Yale School of Medicine’s Department of Immunobiology and the University of Western Australia’s School of Pathology and Laboratory Medicine has uncovered the molecular basis of the development of myeloid leukemia — cancer of the bone marrow and lymph nodes — in mice who have a cancer-causing gene mutation. In the Oct. 19 edition of the journal Cancer Cell, the study, conducted by Sterling Professor of Immunobiology Richard Flavell’s lab at Yale and Wallace Langdon’s lab at the University of Western Australia, describes how increasing activity of the growth factor receptor FLT 3, a part of the cell that receives signals telling the cell to divide, transforms normal stem cells — undeveloped cells that can turn into different specialized cell types — into leukemic stem cells in mice with this mutation.

The study found that mice with a mutation in the c-Cbl gene developed abnormal stem cell growth in the bone marrow that led to lethal myeloid leukemia after six months. When these “knock out” mice that have the gene mutation were mated with mice with deficiencies in a certain growth factor, the mice did not develop leukemia.

“We really made two discoveries,” said postdoctoral fellow and first author Choza Rathinam. “Our group determined that stem cells were responsible for the disease and Langdon’s group identified the FLT 3 ligand [molecule that binds to the FLT 3 receptor].”

The group discovered that the growth factor causes cancer when the c-Cbl gene is mutated because proteins that are normally degraded by the gene are allowed to multiply. Rapid proliferation of cells often leads to cancer, Rathinam said.

The findings have important implications for future drug development.

“If we target the growth factor receptor, there is a good chance that they won’t develop leukemia,” said Langdon.

Researchers are now working to develop an anti-cancer drug to block activity of the growth factor in mice with this gene mutation.

“[This is a] really nice pre-clinical model for the human model… to look at the development of leukemia with mutation and target particular proteins” Langdon said.

Rathinam said the group’s next goal is to infect a mouse with human leukemia of the same gene and then conduct the same experiment.

“We need to find a drug to block the FLT 3 ligand and see if leukemia is cured,” Rathinam said. “Once this is done, we might use the same therapy options to cure people.”

Langdon first discovered the c-Cbl gene while working on retroviruses at the National Institutes of Health during the 1980s. In 2003 he developed “knock out” mice, which contain this cancer-causing gene mutation.

In 2008 Rathinam made a link between the gene mutation and enhanced stem cell growth and activity in the bone marrow and he decided he wanted to apply Langdon’s mutant mouse model to characterize the relationship between stem cells and leukemia, he said.

“With one email and a phone call, we had this miracle,” Rathanim said. “Through international collaboration we can really solve many interesting problems. Science unifies us.”

Yale is now involved in approximately 900 international research projects, Don Filer, associate secretary and director of the Office of International Affairs said.

Comments

  • fnncld

    Great article Jenny! Keep writing!!!

    -Zayde