Scientists at St. Jude Children’s Research Hospital have shown how a protein responsible for adaptation to low oxygen conditions (hypoxia) causes increased expression of fetal hemoglobin (HbF) in adults. The discovery has implications for the treatment of sickle cell disease and beta-thalassemia, serious blood disorders that affect millions of people. The research was published today in Nature.
Hemoglobin is like a protein sponge that absorbs oxygen and allows red blood cells to transport it throughout the body. Adult hemoglobin contains four protein subunits – two beta-globin and two alpha-globin. Beta-globin mutations cause sickle cell disease and beta-thalassemia. But humans have another hemoglobin subunit gene (gamma-globin), which is expressed instead of beta-globin during fetal development. Gamma-globin combines with alpha-globin to form HbF. Normally around birth, gamma-globin expression is turned off and beta-globin is turned on, resulting in the shift from HbF to adult hemoglobin.
“We have known for many years that persistent expression of HbF after birth can alleviate symptoms of sickle cell disease and beta-thalassemia,” said corresponding author Mitchell J. Weiss, MD, Ph.D. ., chairman of the hematology department at St. Jude. “And very high levels of HbF can cure these diseases, despite the presence of defective beta-globin genes. Therefore, many labs are focused on understanding the perinatal switch of gamma to beta-globin gene expression and finding new ways to reverse it with drugs or gene therapies.
Restoration of HbF production in adults
The St. Jude group found that hypoxia-inducible factor 1 (HIF1) directly promotes transcription of the gamma-globin gene to enhance HbF production. HIF1 is an important component of cells’ ability to sense and adapt to hypoxic conditions. Under low oxygen conditions, HIF1 accumulates in many tissues and activates hundreds of genes, including HbF in red blood cells.
First author Ruopeng Feng, Ph.D., a Weiss lab scientist, showed that a drug that activates part of the cellular response to hypoxia inhibits the sickling of red blood cells from adults with sickle cell disease. The drug, a proline hydroxylase inhibitor, caused HIF1 to accumulate, bound a DNA regulatory region near the gamma globin gene, activating its transcription to produce HbF and inhibiting cellular “sickle” . Proline hydroxylase inhibitors are currently in late-stage clinical development for the treatment of anemia associated with chronic kidney disease. These drugs work by stabilizing HIF proteins to stimulate the production of erythropoietin, a hormone that stimulates the production of red blood cells.
“Our results indicate that proline hydroxylase inhibitors may be useful for the treatment of sickle cell disease or beta-thalassemia, where activation of HbF production has therapeutic benefits,” Weiss said. “About 20% of adult patients with sickle cell disease develop kidney failure associated with anemia. Proline hydroxylase inhibitors might serve a dual purpose in these people, by stimulating the production of erythropoietin and HbF.”
Link hypoxic response to HbF
The Nobel Prize in Physiology or Medicine was awarded for the discovery of the HIF pathway in 2019. The current study, led by Weiss’s group, establishes a direct link between this adaptation to hypoxia and the expression of the HbF. This connection explains long-standing clinical observations that HbF is induced during accelerated red blood cell production after exposure to hypoxia or in certain forms of anemia, conditions called “stress erythropoiesis.”
“The identification of gamma-globin as an HIF target gene supports the idea that HbF evolved as a protective mechanism against hypoxia,” Weiss said. “Hemoglobin studies over more than 50 years have established many general principles in biology and medicine. It is exciting and gratifying that research into hemoglobin and globin gene expression continues to yield new clinically relevant findings.”
Authors and funding
Other study authors are Thiyagaraj Mayuranathan, Phillip A. Doerfler, Yichao Li, Yu Yao, Jingjing Zhang, Lance Palmer, Kalin Mayberry, Georgios Christakopoulos, Peng Xu, Chunliang Li, and Yong Cheng, all of St. Jude; Peng Huang and Gerd A. Blobel, Children’s Hospital of Philadelphia and M. Celeste Simon, University of Pennsylvania.
The study was supported by grants from the National Institutes of Health (P01HL053749, R24 DK106766 and P30CA21765), National Institute of Diabetes and Digestive and Kidney Diseases (F32DK118822 and K01DK132453), Cooley’s Anemia Foundation Postdoctoral Research Award , from the Assisi Foundation of Memphis, the St. Jude Collaborative Research Consortium, and ALSAC, St. Jude’s fundraising and outreach organization.