Research Matters at The University of Arizona College of Medicine: Steele Children's Research Center Researchers Discover Protein Plays Role in Sickle Cell Anemia, other Blood Diseases, Suggesting New Therapeutic Approaches

The University of Arizona Health Sciences Center

Research Matters at The University of Arizona College of Medicine

Steele Children's Research Center Researchers Discover Protein Plays Role in
Sickle Cell Anemia, other Blood Diseases, Suggesting New Therapeutic Approaches

Feb. 22, 2006
From: Darci Slaten, (520) 626-7217

Researchers at The University of Arizona Steele Children's Research Center have discovered that the protein Sox6 is responsible for silencing-or turning off-epsilon globin-the embryonic form of beta-globin in hemoglobin. The researchers believe that if epsilon globin can be "re-expressed" (turned back on), it can limit the harmful effects of sickle cell anemia and beta-thalassemia, hereditary blood diseases that affect about 7 percent of the population (primarily African Americans).

The Steele Center research team is led by Murray Brilliant, PhD, Lindholm Professor of Mammalian Genetics, and Orit Cohen-Barak, PhD, research assistant professor in the UA Department of Pediatrics. Dr. Brilliant was the senior author of the study, "Sox6 Directly Silences Epsilon Globin Expression in Definitive Erythropoises," recently published in the peer-reviewed journal PLoS Genetics (available at www.plosgenetics.org).

"Based on this discovery, we now have laid the foundation to begin exploring ways to develop new therapies for sickle cell anemia," Dr. Brilliant says.

Hemoglobin is the protein in red blood cells responsible for transporting oxygen from the lungs to the rest of the body. Normal red blood cells move easily through the blood vessels to deliver oxygen. In sickle cell anemia, genetic mutations in adult beta globin cause the hemoglobin molecules to stick together in long, rigid rods after they release oxygen. These rods cause the red blood cells to become hard and sickle-shaped. When these sickle-shaped red blood cells go through small blood vessels, they clog the flow, depriving the body's cells of blood and oxygen. Side effects include anemia (low blood count) pain episodes, strokes, eye and bone damage.

Hemoglobin consists of "alpha globins" and "beta globins." During development from embryo to adult, beta-globins undergo "beta-globin gene switching"- the transition from embryonic to fetal to adult forms of beta-globin. This transition results in hemoglobins with a different affinity for oxygen. Since sickle cell anemia and beta-thalassemia result from mutations in the adult beta-globin, providing small amounts of normal embryonic or fetal beta-globins can alleviate some of the detrimental effects of the abnormal adult globins, as is found in sickle cell anemia.

This currently is accomplished through a chemotherapeutic approach that uses the drug hydroxyurea. "This chemical causes re-expression of earlier forms of globin that have been turned off in the adult, providing needed relief," says Dr. Brilliant. "But there is a price using hydroxyurea," he says. "Sometimes hydroxyurea works well, but oftentimes there are many negative side effects.

"What we've discovered is a genetic 'switch' to turn the embryonic form of beta-globin back on by turning the Sox6 protein off. So, we've revealed a novel and key component of the switch. By tweaking that switch, we'll be able to at least partially replace the damaged adult beta globin that sickle cell anemia individuals suffer from," he says.

# # #