Researchers show key protein necessary for normal development of red blood cells

October 03, 2005

RICHMOND, Va. (Oct. 3, 2005) - Virginia Commonwealth University researchers studying hemoglobin genes, mutations of which play a role in genetic blood disorders like sickle cell anemia and beta-thalassemia, have shown in studies with mice that the KLF2 protein is crucial for making young red blood cells.

The findings may point researchers to future gene therapies for patients with sickle cell anemia and beta-thalassemia.

In the October issue of Blood, the journal of the American Association for Hematology, researchers demonstrated that a protein called KLF2 regulates the production of embryonic globin genes and the maturation and stability of embryonic red blood cells in a mouse model. Researchers observed that KLF2 is responsible for controlling and "turning on" the embryonic globin gene.

"Understanding how genes are turned on and off, and the switch from the embryonic globin gene to the adult beta-globin gene has clinical relevance to treatment of sickle cell anemia and beta-thalassemia," said Joyce A. Lloyd, Ph.D., associate professor of Human Genetics at VCU, and corresponding author for this study.

"Our findings are significant for future treatment of these blood disorders, potentially using gene therapies and other novel strategies," she said. In gene therapy, a normal DNA is inserted into cells to correct a genetic defect. To correct the defect or mutation, a gene may be replaced, altered or supplemented.

According to Lloyd, the production of blood cells involves a complex differentiation pathway that involves the interaction of many molecular players and proteins.

In humans, there are four globin genes clustered on chromosome 11 in the order in which they are "turned on" or expressed. These genes include the epsilon-globin gene, two gamma-globin genes and the beta-globin gene. Lloyd said that during fetal development, the embryonic epsilon-globin gene is active first, followed by the gamma-globin genes, and finally the adult form, beta-globin takes control following birth.

Lloyd and Priyadarshi Basu, Ph.D., lead investigator at VCU, and the research team compared mice that were missing the gene for KLF2 to normal mice. They found that the KLF2-deficient mice produced embryonic red blood cells that appeared abnormal, were more likely to undergo cell death, and produced significantly lower amounts of globin mRNA than those found in normal mice. Globin mRNA is a key player in gene expression that helps translate the DNA's genetic code.

Lloyd and her colleagues identified that the role of KLF2 for the embryonic epsilon-globin genes is analogous to that of a protein called EKLF. EKLF plays a central role in the developmental regulation of the adult beta-globin gene, and is essential for the maturation and stability of adult red blood cells. Researchers believe that the roles of EKLF and KLF2 may partially overlap in controlling human embryonic and fetal globin gene expression.

This research was supported by a grant from the National Institutes of Health.

Lloyd collaborated with colleagues in the VCU Department of Human Genetics, and the VCU Department of Anatomy and Neurobiology; the Department of Molecular Genetics, Biochemistry and Microbiology at the University of Cincinnati; and the Department of Medicine at the University of California-San Francisco.
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About VCU and the VCU Medical Center: Located on two downtown campuses in Richmond, Va., Virginia Commonwealth University is ranked nationally by the Carnegie Foundation as a top research institution and enrolls more than 28,500 students in more than 181 certificate, undergraduate, graduate, professional and doctoral programs in the arts, sciences and humanities in 15 schools and one college. Forty of the university's programs are unique in Virginia, and 20 graduate and professional programs have been ranked by U.S. News & World Report as among the best of their kind. MCV Hospitals, clinics and the health sciences schools of Virginia Commonwealth University compose the VCU Medical Center, one of the leading academic medical centers in the country. For more, see www.vcu.edu.

Virginia Commonwealth University

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