title: A common signaling pathway is activated in erythroid cells expressing high levels of fetal hemoglobin: a potential role for cAMP-elevating agents in β-globin disorders.
abstract: BACKGROUND
  Although erythroid cells prepared from fetal liver, cord blood, or blood from β-thalassemia patients are known to express fetal hemoglobin at high levels, the underlying mechanisms remain elusive. We previously showed that cyclic nucleotides such as cAMP and cGMP induce fetal hemoglobin expression in primary erythroid cells. Here we report that cAMP signaling contributes to high-level fetal hemoglobin expression in erythroid cells prepared from cord blood and β-thalassemia.
  
  
  METHODS
  The status of the cAMP signaling pathway was investigated using primary erythroid cells prepared from cord blood and the mononuclear cells of patients with β-thalassemia; erythroid cells from adult bone marrow mononuclear cells served as the control.
  
  
  RESULTS
  We found that intracellular cAMP levels were higher in erythroid cells from cord blood and β-thalassemia than from adult bone marrow. Protein kinase A activity levels and cAMP-response element binding protein phosphorylation were higher in erythroid cells from cord blood or β-thalassemia than in adult bone marrow progenitors. Mitogen-activated protein kinase pathways, which play a role in fetal hemoglobin expression, were not consistently activated in cord blood or β-thalassemia erythroid cells. When cAMP signaling was activated in adult erythroid cells, fetal hemoglobin was induced at high levels and associated with reduced expression of BCL11A, a silencer of the β-globin gene.
  
  
  CONCLUSIONS
  These results suggest that activated cAMP signaling may be a common mechanism among erythroid cells with high fetal hemoglobin levels, in part because of downregulation of BCL11A. Activation of the cAMP signaling pathway with cAMP-elevating agents may prove to be an important signaling mechanism to reactivate fetal hemoglobin expression in erythroid cells.
authors.affiliation: Department of Anesthesiology and Perioperative Medicine, Georgia Regents University, Augusta, GA, USA.
authors.forename: Tohru
authors.initials: T
authors.lastname: Ikuta
authors.affiliation: Department of Anesthesiology and Perioperative Medicine, Georgia Regents University, Augusta, GA, USA.
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Kuroyanagi
authors.affiliation: Department of Anesthesiology and Perioperative Medicine, Georgia Regents University, Augusta, GA, USA.
authors.forename: Nadine
authors.initials: N
authors.lastname: Odo
authors.affiliation: Department of Physiology, Medical College of Georgia, Georgia Regents University, Augusta, GA, USA.
authors.forename: Siyang
authors.initials: S
authors.lastname: Liu
keywords: cAMP; cord blood; fetal hemoglobin; signaling; β-globin disorders; β-thalassemia