Journal
SCIENCE
Volume 334, Issue 6058, Pages 993-996Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/science.1211053
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Funding
- NIH
- National Cancer Institute (NCI)
- Marie Betzner Morrow Endowment
- National Institute of Diabetes and Digestive and Kidney Diseases
- National Research Service Award/NCI
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Persistence of human fetal hemoglobin (HbF, alpha(2)gamma(2)) in adults lessens the severity of sickle cell disease (SCD) and the beta-thalassemias. Here, we show that the repressor BCL11A is required in vivo for silencing of gamma-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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