title: Correction of sickle cell disease in adult mice by interference with fetal hemoglobin silencing.
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.
authors: Division of Hematology/Oncology, Children's Hospital Boston and Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
authors: Jian
authors: J
authors: Xu
authors: Cong
authors: C
authors: Peng
authors: Vijay G
authors: VG
authors: Sankaran
authors: Zhen
authors: Z
authors: Shao
authors: Erica B
authors: EB
authors: Esrick
authors: Bryan G
authors: BG
authors: Chong
authors: Gregory C
authors: GC
authors: Ippolito
authors: Yuko
authors: Y
authors: Fujiwara
authors: Benjamin L
authors: BL
authors: Ebert
authors: Philip W
authors: PW
authors: Tucker
authors: Stuart H
authors: SH
authors: Orkin
mesh_terms: D000755:Anemia, Sickle Cell / Q000097:blood / Q000235:genetics* / Q000473:pathology / Q000628:therapy*; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000502:physiology*; D019175:DNA Methylation; D004268:DNA-Binding Proteins; D004622:Embryo, Mammalian; D044127:Epigenesis, Genetic; D041905:Erythroid Cells / Q000378:metabolism; D005319:Fetal Hemoglobin / Q000235:genetics* / Q000378:metabolism; D005786:Gene Expression Regulation; D020868:Gene Silencing; D006657:Histones / Q000378:metabolism; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D058990:Molecular Targeted Therapy; D009687:Nuclear Proteins / Q000235:genetics / Q000502:physiology*; D012097:Repressor Proteins; D055545:gamma-Globins / Q000235:genetics*
chemical_list: C407733:Bcl11a protein, mouse; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D006657:Histones; D009687:Nuclear Proteins; D012097:Repressor Proteins; D055545:gamma-Globins; D005319:Fetal Hemoglobin