As a student at the University of Crete in Greece—and the first member of his family to attend college—Iannis Aifantis had hoped to make a difference in the world by becoming a medical doctor. Instead, he found his way to the…
As a student at the University of Crete in Greece—and the first member of his family to attend college—Iannis Aifantis had hoped to make a difference in the world by becoming a medical doctor. Instead, he found his way to the laboratory, where his work is now helping doctors understand T cell acute lymphoblastic leukemia. The disease, which afflicts thousands of children in the United States each year, can attack different vital organs, including the central nervous system, with dire consequences. Although current treatments can induce a remission in some patients, as many as 25 percent of patients experience relapse that can be fatal. Aifantis credits a combination of "luck and an inability to take exams" for redirecting him from medicine to pursue a Ph.D. at the University of Paris and postdoctoral research at the Dana-Farber Cancer Institute in Boston, where he immersed himself in the mysteries of the developing immune system. Today, Aifantis is an immunologist at the New York University Langone Medical Center, where he is teasing out the subtle molecular signaling events that shape how blood stem cells mature into a variety of cells in the immune system. He is also studying how some of those cells can go bad, causing T cell acute lymphoblastic leukemia. "We are trying several potentially translational approaches," Aifantis explains. He notes that as a stem cell becomes more specialized—maturing, for instance, into a neuron or blood cell—the line between normal development and cancer becomes thin. "We are interested in finding these tipping points, and we think we can learn a lot about how these changes occur by using the immune system as our model," he says. Specifically, Aifantis is studying hematopoietic stem cells, which give rise to all the cell types found in the blood. One of the cell types, called T cells, helps the immune system recognize and respond to pathogens. Immature T cells migrate to the thymus gland where they grow and differentiate into different subtypes of T cells, a process that Aifantis found is dependent on the interplay of several critical cell signaling pathways, including Notch and Hedgehog. These cell-to-cell communication pathways can turn genes on or off and influence how cells become one kind of cell or another, both in early development and later in life. He was among the first to explore Notch signaling in the context of T cell development and leukemia. The gene encoding a key Notch protein was known to be mutated in the majority of patients afflicted with the disease. Aifantis found that the mutated protein interferes with normal communication between the Notch pathway and other signaling pathways to cause T cell acute lymphoblastic leukemia. He also found that the disease could be suppressed in cells in the laboratory through genetic manipulation and drugs, two strategies that one day may be developed into better treatments for people with T cell acute lymphoblastic leukemia. "In principle, it works beautifully," says Aifantis. The catch, however, is that the Notch pathway is important for systems beyond blood. "The challenge is generating inhibitors with minimal side effects." To address the issue, Aifantis plans to take his work from the culture dish to preclinical animal models of the disease. One of his primary goals is to model leukemia in the mouse by creating genetically engineered mice that carry the same genetic mutations found in humans who have the disease. Those mice can then be used as tools to screen potential drugs and to develop strategies that can selectively block Notch's role in causing cancer. Aifantis's work is already hinting at new treatments for T cell acute lymphoblastic leukemia. His group recently discovered a close connection between Notch activation and enzymes of the ubiquitin-proteasome pathway, and they are experimenting on ways that can promote the Notch oncoprotein degradation. Also, his laboratory identified a single adhesion molecule, a protein that helps cells bind to one another, and proved that it is essential for allowing diseased cells to enter the central nervous system. Designing an inhibitor to keep diseased cells out, says Aifantis, may now be possible. For patients suffering from T cell acute lymphoblastic leukemia, that would make quite a difference indeed.