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Forced chromatin looping raises fetal hemoglobin in adult sickle cells to higher levels than pharmacologic inducers.
Breda, Laura; Motta, Irene; Lourenco, Silvia; Gemmo, Chiara; Deng, Wulan; Rupon, Jeremy W; Abdulmalik, Osheiza Y; Manwani, Deepa; Blobel, Gerd A; Rivella, Stefano.
Afiliación
  • Breda L; Department of Pediatrics, Division of Hematology-Oncology, Children's Blood and Cancer Foundation Laboratories, Weill Cornell Medical College, New York, NY; Department of Pediatrics, Division of Hematology, Children's Hospital of Philadelphia, Philadelphia, PA;
  • Motta I; Department of Pediatrics, Division of Hematology-Oncology, Children's Blood and Cancer Foundation Laboratories, Weill Cornell Medical College, New York, NY; Department of Clinical Science and Community Health, University of Milan, Milan, Italy;
  • Lourenco S; Department of Pediatrics, Division of Hematology-Oncology, Children's Blood and Cancer Foundation Laboratories, Weill Cornell Medical College, New York, NY; Department of Pediatrics, Division of Hematology, Children's Hospital of Philadelphia, Philadelphia, PA;
  • Gemmo C; Department of Pediatrics, Division of Hematology-Oncology, Children's Blood and Cancer Foundation Laboratories, Weill Cornell Medical College, New York, NY;
  • Deng W; Transcription Imaging Consortium, Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, VA; and.
  • Rupon JW; Department of Pediatrics, Division of Hematology, Children's Hospital of Philadelphia, Philadelphia, PA;
  • Abdulmalik OY; Department of Pediatrics, Division of Hematology, Children's Hospital of Philadelphia, Philadelphia, PA;
  • Manwani D; Department of Pediatrics, Albert Einstein College of Medicine, Children's Hospital at Montefiore, Bronx, NY.
  • Blobel GA; Department of Pediatrics, Division of Hematology, Children's Hospital of Philadelphia, Philadelphia, PA;
  • Rivella S; Department of Pediatrics, Division of Hematology-Oncology, Children's Blood and Cancer Foundation Laboratories, Weill Cornell Medical College, New York, NY; Department of Pediatrics, Division of Hematology, Children's Hospital of Philadelphia, Philadelphia, PA;
Blood ; 128(8): 1139-43, 2016 08 25.
Article en En | MEDLINE | ID: mdl-27405777
Overcoming the silencing of the fetal γ-globin gene has been a long-standing goal in the treatment of sickle cell disease (SCD). The major transcriptional enhancer of the ß-globin locus, called the locus control region (LCR), dynamically interacts with the developmental stage-appropriate ß-type globin genes via chromatin looping, a process requiring the protein Ldb1. In adult erythroid cells, the LCR can be redirected from the adult ß- to the fetal γ-globin promoter by tethering Ldb1 to the human γ-globin promoter with custom-designed zinc finger (ZF) proteins (ZF-Ldb1), leading to reactivation of γ-globin gene expression. To compare this approach to pharmacologic reactivation of fetal hemoglobin (HbF), hematopoietic cells from patients with SCD were treated with a lentivirus expressing the ZF-Ldb1 or with chemical HbF inducers. The HbF increase in cells treated with ZF-Ldb1 was more than double that observed with decitabine and pomalidomide; butyrate had an intermediate effect whereas tranylcypromine and hydroxyurea showed relatively low HbF reactivation. ZF-Ldb1 showed comparatively little toxicity, and reduced sickle hemoglobin (HbS) synthesis as well as sickling of SCD erythroid cells under hypoxic conditions. The efficacy and low cytotoxicity of lentiviral-mediated ZF-Ldb1 gene transfer compared with the drug regimens support its therapeutic potential for the treatment of SCD.
Asunto(s)

Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Hemoglobina Fetal / Cromatina / Anemia de Células Falciformes Límite: Adult / Humans Idioma: En Revista: Blood Año: 2016 Tipo del documento: Article

Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Hemoglobina Fetal / Cromatina / Anemia de Células Falciformes Límite: Adult / Humans Idioma: En Revista: Blood Año: 2016 Tipo del documento: Article