Strict in vivo specificity of the Bcl11a erythroid enhancer

被引：37
作者：
Smith, Elenoe C. [1 ,2 ,3 ,4 ]
Luc, Sidinh [1 ,2 ,3 ,4 ]
Croney, Donyell M. [1 ,2 ,3 ,4 ]
Woodworth, Mollie B. [3 ,5 ,6 ]
Greig, Luciano C. [3 ,5 ,6 ]
Fujiwara, Yuko [1 ,2 ,3 ,4 ,7 ]
Minh Nguyen [1 ,2 ,3 ,4 ]
Sher, Falak [1 ,2 ,3 ,4 ]
Macklis, Jeffrey D. [3 ,5 ,6 ]
Bauer, Daniel E. [1 ,2 ,3 ,4 ]
Orkin, Stuart H. [1 ,2 ,3 ,4 ,7 ]
机构：
[1] Boston Childrens Hosp, Div Hematol Oncol, Boston, MA USA
[2] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA
[3] Harvard Univ, Harvard Stem Cell Inst, Cambridge, MA 02138 USA
[4] Harvard Med Sch, Dept Pediat, Boston, MA USA
[5] Harvard Univ, Dept Stem Cell & Regenerat Biol, Cambridge, MA 02138 USA
[6] Harvard Univ, Ctr Brain Sci, Cambridge, MA 02138 USA
[7] Howard Hughes Med Inst, Boston, MA 02115 USA
来源：
BLOOD | 2016年 / 128卷 / 19期
基金：
美国国家卫生研究院;
关键词：
SICKLE-CELL-DISEASE; FETAL-HEMOGLOBIN; GLOBIN; GENE; STEM; EXPRESSION; PHENOTYPE; DEFECTS; PROTEIN; EKLF;
D O I：
10.1182/blood-2016-08-736249
中图分类号：
R5 [内科学];
学科分类号：
1002 ; 100201 ;
摘要：
BCL11A, a repressor of human fetal (gamma-) globin expression, is required for immune and hematopoietic stem cell functions and brain development. Regulatory sequences within the gene, which are subject to genetic variation affecting fetal globin expression, display hallmarks of an erythroid enhancer in cell lines and transgenic mice. As such, this enhancer is a novel, attractive target for therapeutic gene editing. To explore the roles of such sequences in vivo, we generated mice in which the orthologous 10-kb intronic sequences were removed. Bcl11a enhancer-deleted mice, Bcl11a(Delta enh), phenocopy the BCL11A-null state with respect to alterations of globin expression, yet are viable and exhibit no observable blood, brain, or other abnormalities. These preclinical findings provide strong in vivo support for genetic modification of the enhancer for therapy of hemoglobin disorders.
引用
收藏
页码：2338 / 2342
页数：5
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