title: Induction of human fetal hemoglobin via the NRF2 antioxidant response signaling pathway.
abstract: Although hematopoietic stem cell transplantation and gene therapy have the potential to cure β-thalassemia and sickle cell disease, they are not currently available to most people with these diseases. In the near term, pharmacologic induction of fetal hemoglobin (HbF) may offer the best possibility for safe, effective, and widely available therapy. In an effort to define new pathways for targeted drug development for HbF induction, we evaluated the nuclear factor erythroid 2-related factor 2 (NRF2) antioxidant response element signaling pathway. We found that 3 well-known activators of this pathway increased γ-globin mRNA at nontoxic doses in K562 cells. Tert-butylhydroquinone (tBHQ), the most active of these compounds, increased cellular levels and nuclear translocation of NRF2 and binding of NRF2 to the γ-globin promoter. siRNA knockdown of NRF2 inhibited γ-globin induction by tBHQ. When tested in human primary erythroid cells, tBHQ induced NRF2 binding to the γ-globin promoter, increased γ-globin mRNA and HbF, and suppressed β-globin mRNA and HbA, resulting in a > 3-fold increase in the percentage of HbF. These results suggest that drugs that activate the NRF2/antioxidant response element signaling pathway have the potential to induce therapeutic levels of HbF in people with β-hemoglobinopathies.
authors.affiliation: Department of Pharmacology & Toxicology.
authors.forename: Elizabeth R
authors.initials: ER
authors.lastname: Macari
authors.forename: Christopher H
authors.initials: CH
authors.lastname: Lowrey
mesh_terms: D000975:Antioxidants / Q000627:therapeutic use*; D015153:Blotting, Western; D002454:Cell Differentiation; D047369:Chromatin Immunoprecipitation; D024202:Electrophoretic Mobility Shift Assay; D041905:Erythroid Cells / Q000378:metabolism; D005319:Fetal Hemoglobin / Q000378:metabolism*; D006801:Humans; D006873:Hydroquinones / Q000627:therapeutic use*; D020014:K562 Cells; D008156:Luciferases / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D021381:Protein Transport; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D020218:Response Elements; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects*; D055544:beta-Globins; D017086:beta-Thalassemia / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D055545:gamma-Globins / Q000235:genetics* / Q000378:metabolism
chemical_list: D000975:Antioxidants; D006873:Hydroquinones; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D055544:beta-Globins; D055545:gamma-Globins; D005319:Fetal Hemoglobin; C018855:2-tert-butylhydroquinone; D008156:Luciferases