Correction of sickle cell disease in adult mice by interference with fetal hemoglobin silencing

Science. 2011 Nov 18;334(6058):993-6. doi: 10.1126/science.1211053. Epub 2011 Oct 13.

Abstract

Persistence of human fetal hemoglobin (HbF, α(2)γ(2)) in adults lessens the severity of sickle cell disease (SCD) and the β-thalassemias. Here, we show that the repressor BCL11A is required in vivo for silencing of γ-globin expression in adult animals, yet dispensable for red cell production. BCL11A serves as a barrier to HbF reactivation by known HbF inducing agents. In a proof-of-principle test of BCL11A as a potential therapeutic target, we demonstrate that inactivation of BCL11A in SCD transgenic mice corrects the hematologic and pathologic defects associated with SCD through high-level pancellular HbF induction. Thus, interference with HbF silencing by manipulation of a single target protein is sufficient to reverse SCD.

Publication types

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

MeSH terms

  • Anemia, Sickle Cell / blood
  • Anemia, Sickle Cell / genetics*
  • Anemia, Sickle Cell / pathology
  • Anemia, Sickle Cell / therapy*
  • Animals
  • Carrier Proteins / genetics
  • Carrier Proteins / physiology*
  • DNA Methylation
  • DNA-Binding Proteins
  • Embryo, Mammalian
  • Epigenesis, Genetic
  • Erythroid Cells / metabolism
  • Fetal Hemoglobin / genetics*
  • Fetal Hemoglobin / metabolism
  • Gene Expression Regulation*
  • Gene Silencing*
  • Histones / metabolism
  • Humans
  • Mice
  • Mice, Knockout
  • Mice, Transgenic
  • Molecular Targeted Therapy
  • Nuclear Proteins / genetics
  • Nuclear Proteins / physiology*
  • gamma-Globins / genetics*

Substances

  • Bcl11a protein, mouse
  • Carrier Proteins
  • DNA-Binding Proteins
  • Histones
  • Nuclear Proteins
  • gamma-Globins
  • Fetal Hemoglobin