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Globin vector regulatory elements are active in early hematopoietic progenitor cells

The globin genes are archetypal tissue-specific genes that are silent in most tissues but for late-stage erythroblasts upon terminal erythroid differentiation. The transcriptional activation of the β-globin gene is under the control of proximal and distal regulatory elements located on chromosome 11...

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Autores principales: Cabriolu, Annalisa, Odak, Ashlesha, Zamparo, Lee, Yuan, Han, Leslie, Christina S., Sadelain, Michel
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society of Gene & Cell Therapy 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9171148/
https://www.ncbi.nlm.nih.gov/pubmed/35247584
http://dx.doi.org/10.1016/j.ymthe.2022.02.028
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author Cabriolu, Annalisa
Odak, Ashlesha
Zamparo, Lee
Yuan, Han
Leslie, Christina S.
Sadelain, Michel
author_facet Cabriolu, Annalisa
Odak, Ashlesha
Zamparo, Lee
Yuan, Han
Leslie, Christina S.
Sadelain, Michel
author_sort Cabriolu, Annalisa
collection PubMed
description The globin genes are archetypal tissue-specific genes that are silent in most tissues but for late-stage erythroblasts upon terminal erythroid differentiation. The transcriptional activation of the β-globin gene is under the control of proximal and distal regulatory elements located on chromosome 11p15.4, including the β-globin locus control region (LCR). The incorporation of selected LCR elements in lentiviral vectors encoding β and β-like globin genes has enabled successful genetic treatment of the β-thalassemias and sickle cell disease. However, recent occurrences of benign clonal expansions in thalassemic patients and myelodysplastic syndrome in patients with sickle cell disease call attention to the non-erythroid functions of these powerful vectors. Here we demonstrate that lentivirally encoded LCR elements, in particular HS1 and HS2, can be activated in early hematopoietic cells including hematopoietic stem cells and myeloid progenitors. This activity is position-dependent and results in the transcriptional activation of a nearby reporter gene in these progenitor cell populations. We further show that flanking a globin vector with an insulator can effectively restrain this non-erythroid activity without impairing therapeutic globin expression. Globin lentiviral vectors harboring powerful LCR HS elements may thus expose to the risk of trans-activating cancer-related genes, which can be mitigated by a suitable insulator.
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spelling pubmed-91711482023-06-01 Globin vector regulatory elements are active in early hematopoietic progenitor cells Cabriolu, Annalisa Odak, Ashlesha Zamparo, Lee Yuan, Han Leslie, Christina S. Sadelain, Michel Mol Ther Original Article The globin genes are archetypal tissue-specific genes that are silent in most tissues but for late-stage erythroblasts upon terminal erythroid differentiation. The transcriptional activation of the β-globin gene is under the control of proximal and distal regulatory elements located on chromosome 11p15.4, including the β-globin locus control region (LCR). The incorporation of selected LCR elements in lentiviral vectors encoding β and β-like globin genes has enabled successful genetic treatment of the β-thalassemias and sickle cell disease. However, recent occurrences of benign clonal expansions in thalassemic patients and myelodysplastic syndrome in patients with sickle cell disease call attention to the non-erythroid functions of these powerful vectors. Here we demonstrate that lentivirally encoded LCR elements, in particular HS1 and HS2, can be activated in early hematopoietic cells including hematopoietic stem cells and myeloid progenitors. This activity is position-dependent and results in the transcriptional activation of a nearby reporter gene in these progenitor cell populations. We further show that flanking a globin vector with an insulator can effectively restrain this non-erythroid activity without impairing therapeutic globin expression. Globin lentiviral vectors harboring powerful LCR HS elements may thus expose to the risk of trans-activating cancer-related genes, which can be mitigated by a suitable insulator. American Society of Gene & Cell Therapy 2022-06-01 2022-03-02 /pmc/articles/PMC9171148/ /pubmed/35247584 http://dx.doi.org/10.1016/j.ymthe.2022.02.028 Text en © 2022 The Authors https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Original Article
Cabriolu, Annalisa
Odak, Ashlesha
Zamparo, Lee
Yuan, Han
Leslie, Christina S.
Sadelain, Michel
Globin vector regulatory elements are active in early hematopoietic progenitor cells
title Globin vector regulatory elements are active in early hematopoietic progenitor cells
title_full Globin vector regulatory elements are active in early hematopoietic progenitor cells
title_fullStr Globin vector regulatory elements are active in early hematopoietic progenitor cells
title_full_unstemmed Globin vector regulatory elements are active in early hematopoietic progenitor cells
title_short Globin vector regulatory elements are active in early hematopoietic progenitor cells
title_sort globin vector regulatory elements are active in early hematopoietic progenitor cells
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9171148/
https://www.ncbi.nlm.nih.gov/pubmed/35247584
http://dx.doi.org/10.1016/j.ymthe.2022.02.028
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