Monday, Aug. 6, 2007
Commonwealth University researchers studying hemoglobin genes, mutations of
which play a role in genetic blood disorders like sickle cell anemia and
beta-thalassemia, have identified two proteins that
are responsible for regulating overlapping groups of genes during the
development of red blood cells.
findings may point researchers to future gene therapies for patients with
sickle cell anemia and beta-thalassemia.
In an article
pre-published online Aug. 3 as a First Edition Paper in the journal Blood, the
journal of the American Association for Hematology, researchers reported that a
protein called KLF2 coordinates with a related and well-studied transcription
factor, EKLF, in the regulation of embryonic globin genes responsible for the
development of mouse embryonic red blood cells.
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. KLF2 is a protein crucial
for making embryonic red blood cells.
"If EKLF and KLF2 can turn on the
embryonic globin genes in adult cells – we don't know if this is true yet -
then these findings may provide a gene therapy approach for treating sickle
cell anemia and beta-thalassemia. It is well-established that the expression of
embryonic globin genes can help ameliorate these diseases," said Joyce A. Lloyd, Ph.D.,
associate professor of human genetics at the VCU Massey Cancer Center, and
corresponding author for this study.
team studied gene expression and red blood cell development in the mouse
embryo. They used mouse
embryos missing both the KLF2 and EKLF genes to show that embryonic globin
expression is severely reduced, and that the embryos therefore are anemic,
compared to mice missing KLF2 or EKLF alone.
likely means that EKLF and KLF2, which are related transcription factors,
regulate overlapping groups of genes in developing red blood cells. In the absence
of both factors, they cannot compensate for each other, causing more serious
defects in red blood cell development," Lloyd said.
to Lloyd, the production of blood cells involves a complex differentiation
pathway with interactions between many molecular players and proteins.
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
how genes are regulated or turned on and off is critical. In gene therapy, a
normal gene can be inserted into cells to correct a genetic defect. However,
according to Lloyd, in this case, the goal would be to insert a transcription
factor into adult cells that would turn on an existing, silenced embryonic
research was supported by a grant from the National Institutes of Health.
collaborated with Jack Haar, Ph.D., professor of anatomy and neurobiology in
the VCU School of Medicine; Priyadarshi
Basu, Ph.D., a former postdoctoral fellow at VCU; and Tina Lung, who recently
earned her masters degree. Additionally, colleagues from the Department of
Molecular Genetics, Biochemistry and Microbiology at the University of Cincinnati also contributed to this work.
About VCU and VCU Medical Center
Virginia Commonwealth University is a major, urban public research university with national and international rankings in sponsored research. Located in downtown Richmond, VCU enrolls more than 31,000 students in 226 degree and certificate programs in the arts, sciences and humanities. Sixty-seven of the programs are unique in Virginia, many of them crossing the disciplines of VCU’s 13 schools and one college. MCV Hospitals and the health sciences schools of Virginia Commonwealth University comprise VCU Medical Center, one of the nation’s leading academic medical centers. For more, see www.vcu.edu.
About the VCU Massey Cancer Center
VCU Massey Cancer Center is one of only 68 National Cancer Institute-designated institutions in the country that leads and shapes America’s cancer research efforts. Working with all kinds of cancers, Massey conducts basic, translational and clinical cancer research, provides state-of-the-art treatments and clinical trials, and promotes cancer prevention and education. Since 1974, Massey has served as an internationally recognized center of excellence. It offers the most cancer clinical trials in Virginia and serves patients at 10 locations. Its 1,000-plus researchers, clinicians and staff members are dedicated to improving the quality of human life by developing and delivering effective means to prevent, control and ultimately cure cancer. Visit Massey online at www.massey.vcu.edu or call 877-4-MASSEY for more information.