Division of Hematology/Oncology, Children's Hospital Boston and Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
Science. 2011 Nov 18;334(6058):993-6. doi: 10.1126/science.1211053. Epub 2011 Oct 13.
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.
人体内胎儿血红蛋白（HbF，α(2)γ(2)）的持续存在可减轻镰状细胞病（SCD）和β-地中海贫血的严重程度。在这里，我们表明，在体内，抑制蛋白 BCL11A 对于成年动物中γ-珠蛋白表达的沉默是必需的，但对于红细胞的生成是可有可无的。BCL11A 是已知的 HbF 诱导剂重新激活 HbF 的障碍。在 BCL11A 作为一种潜在治疗靶点的原理验证测试中，我们证明了 SCD 转基因小鼠中 BCL11A 的失活通过高水平的全细胞 HbF 诱导纠正了与 SCD 相关的血液学和病理学缺陷。因此，通过操纵单个靶蛋白来干扰 HbF 沉默足以逆转 SCD。
