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

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

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  • 1Division of Hematology/Oncology, Children's Hospital Boston and Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.

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.

PMID:
21998251
[PubMed - indexed for MEDLINE]
PMCID:
PMC3746545
Free PMC Article
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