Journal
BLOOD
Volume 128, Issue 19, Pages 2338-2342Publisher
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2016-08-736249
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Funding
- Jane Coffin Childs Memorial Fund for Medical Research Fellowship
- Burroughs Wellcome Fund Postdoctoral Enrichment Program Award
- Leukemia & Lymphoma Society Fellow Award
- National Institute of Neurological Disorders and Stroke
- National Institutes of Health individual National Research Service Awards [NS064730, NS080343]
- National Institute of Neurological Disorders and Stroke, National Institutes of Health [NS075672, NS045523, NS041590, NS093376]
- DEARS Foundation
- Harvard Medical Scientist Training Program
- National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health [K08DK093705, R03DK109232]
- Charles H. Hood Foundation
- American Society of Hematology
- Burroughs Wellcome Fund
- Cooley's Anemia Foundation
- National Heart, Lung, and Blood Institute, National Institutes of Health [P01HL032262]
- National Institute of Diabetes and Digestive and Kidney Diseases (Center of Excellence in Molecular Hematology) [P30DK049216]
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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.
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