Globin vector regulatory elements are active in early hematopoietic progenitor cells Journal Article


Authors: Cabriolu, A.; Odak, A.; Zamparo, L.; Yuan, H.; Leslie, C. S.; Sadelain, M.
Article Title: Globin vector regulatory elements are active in early hematopoietic progenitor cells
Abstract: 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. © 2022 The Authors
Keywords: controlled study; protein expression; human cell; genetics; nonhuman; mouse; metabolism; animal tissue; transcription initiation; cell line; animal experiment; cell population; gene vector; genetic vectors; gene therapy; thalassemia; globin; hemoglobin beta chain; globin gene; beta-globins; hematopoietic stem cells; reporter gene; hematopoietic stem cell; c57bl 6 mouse; myeloid progenitor cell; globins; sickle cell disease; sickle cell anemia; hematopoietic progenitor cells; anemia, sickle cell; hemoglobinopathies; lentiviral vector; procedures; locus control region; genetic therapy; humans; human; male; female; article; beta-globin gene; atac-seq; hs 1.lu cell line; erythroid expression; hs 2.lu cell line
Journal Title: Molecular Therapy
Volume: 30
Issue: 6
ISSN: 1525-0016
Publisher: Nature Publishing Group  
Date Published: 2022-06-01
Start Page: 2199
End Page: 2209
Language: English
DOI: 10.1016/j.ymthe.2022.02.028
PUBMED: 35247584
PROVIDER: scopus
PMCID: PMC9171148
DOI/URL:
Notes: Article -- Export Date: 1 July 2022 -- Source: Scopus
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MSK Authors
  1. Michel W J Sadelain
    538 Sadelain
  2. Christina Leslie
    159 Leslie
  3. Han   Yuan
    7 Yuan
  4. Ashlesha Odak
    8 Odak