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

ABSTRACT: Persistence of human fetal hemoglobin (HbF, ?(2)?(2)) in adults lessens the severity of sickle cell disease (SCD) and the ?-thalassemias. Here, we show that the repressor BCL11A is required in vivo for silencing of ?-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.

SUBMITTER: Xu J

PROVIDER: S-EPMC3746545 | biostudies-literature | 2011 Nov

REPOSITORIES: biostudies-literature

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

Xu Jian J Peng Cong C Sankaran Vijay G VG Shao Zhen Z Esrick Erica B EB Chong Bryan G BG Ippolito Gregory C GC Fujiwara Yuko Y Ebert Benjamin L BL Tucker Philip W PW Orkin Stuart H SH

Science (New York, N.Y.) 20111013 6058

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 trans ...[more]

PMID: 21998251

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