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

Jian Xu; Cong Peng; Vijay G. Sankaran; Zhen Shao; Erica B. Esrick; Bryan G. Chong; Gregory C. Ippolito; Yuko Fujiwara; Benjamin L. Ebert; Philip W. Tucker; Stuart H. Orkin

doi:10.1126/science.1211053

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

Jian Xu, Cong Peng, Vijay G. Sankaran, Zhen Shao, Erica B. Esrick, Bryan G. Chong, Gregory C. Ippolito, Yuko Fujiwara, Benjamin L. Ebert, Philip W. Tucker, Stuart H. Orkin

Research output: Contribution to journal › Article › peer-review

261 Scopus citations

Abstract

Persistence of human fetal hemoglobin (HbF, α₂γ 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.

Original language	English (US)
Pages (from-to)	993-996
Number of pages	4
Journal	Science
Volume	334
Issue number	6058
DOIs	https://doi.org/10.1126/science.1211053
State	Published - Nov 18 2011

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title = "Correction of sickle cell disease in adult mice by interference with fetal hemoglobin silencing",

abstract = "Persistence of human fetal hemoglobin (HbF, α2γ 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 = "Jian Xu and Cong Peng and Sankaran, {Vijay G.} and Zhen Shao and Esrick, {Erica B.} and Chong, {Bryan G.} and Ippolito, {Gregory C.} and Yuko Fujiwara and Ebert, {Benjamin L.} and Tucker, {Philip W.} and Orkin, {Stuart H.}",

year = "2011",

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doi = "10.1126/science.1211053",

language = "English (US)",

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T1 - Correction of sickle cell disease in adult mice by interference with fetal hemoglobin silencing

AU - Xu, Jian

AU - Peng, Cong

AU - Sankaran, Vijay G.

AU - Shao, Zhen

AU - Esrick, Erica B.

AU - Chong, Bryan G.

AU - Ippolito, Gregory C.

AU - Fujiwara, Yuko

AU - Ebert, Benjamin L.

AU - Tucker, Philip W.

AU - Orkin, Stuart H.

PY - 2011/11/18

Y1 - 2011/11/18

N2 - Persistence of human fetal hemoglobin (HbF, α2γ 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.

AB - Persistence of human fetal hemoglobin (HbF, α2γ 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.

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

Abstract

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