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

  • Xu J
  • Peng C
  • Sankaran V
 et al. 
  • 129


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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.

Author-supplied keywords

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

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  • Jian Xu

  • Cong Peng

  • Vijay G Sankaran

  • Zhen Shao

  • Erica B Esrick

  • Bryan G Chong

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