HIF1alpha synergizes with glucocorticoids to promote BFU-E progenitor self-renewal

Blood. 2011 Mar 24;117(12):3435-44. doi: 10.1182/blood-2010-07-295550. Epub 2010 Dec 21.


With the aim of finding small molecules that stimulate erythropoiesis earlier than erythropoietin and that enhance erythroid colony-forming unit (CFU-E) production, we studied the mechanism by which glucocorticoids increase CFU-E formation. Using erythroid burst-forming unit (BFU-E) and CFU-E progenitors purified by a new technique, we demonstrate that glucocorticoids stimulate the earliest (BFU-E) progenitors to undergo limited self-renewal, which increases formation of CFU-E cells > 20-fold. Interestingly, glucocorticoids induce expression of genes in BFU-E cells that contain promoter regions highly enriched for hypoxia-induced factor 1α (HIF1α) binding sites. This suggests activation of HIF1α may enhance or replace the effect of glucocorticoids on BFU-E self-renewal. Indeed, HIF1α activation by a prolyl hydroxylase inhibitor (PHI) synergizes with glucocorticoids and enhances production of CFU-Es 170-fold. Because PHIs are able to increase erythroblast production at very low concentrations of glucocorticoids, PHI-induced stimulation of BFU-E progenitors thus represents a conceptually new therapeutic window for treating erythropoietin-resistant anemia.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acids, Dicarboxylic / pharmacology
  • Animals
  • Binding Sites
  • Cell Differentiation / drug effects
  • Cell Differentiation / physiology
  • Cell Proliferation / drug effects*
  • Cell Separation
  • Cells, Cultured
  • Drug Evaluation, Preclinical
  • Drug Synergism
  • Embryo, Mammalian
  • Enzyme Inhibitors / pharmacology
  • Erythroid Precursor Cells / drug effects*
  • Erythroid Precursor Cells / physiology*
  • Fetus / cytology
  • Flow Cytometry
  • Glucocorticoids / pharmacology*
  • Hypoxia-Inducible Factor 1, alpha Subunit / agonists*
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
  • Hypoxia-Inducible Factor 1, alpha Subunit / physiology
  • Liver / cytology
  • Liver / embryology
  • Mice
  • Procollagen-Proline Dioxygenase / antagonists & inhibitors
  • Response Elements / drug effects
  • Response Elements / genetics


  • Amino Acids, Dicarboxylic
  • Enzyme Inhibitors
  • Glucocorticoids
  • Hif1a protein, mouse
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Procollagen-Proline Dioxygenase
  • oxalylglycine