Stefan Stein, Marion Gabriele Ott, Stephan Schultze-Straßer, Anna Jauch, Barbara Burwinkel, Andrea Kinner, Manfred Schmidt, Alwin Krämer, Joachim Schwäble, Hanno Glimm, Ulrike Köhl, Carolin Preiss, Claudia Ball, Hans Martin, Gudrun Göhring, Kerstin Schwarzwaelder, Wolf-Karsten Hofmann, Kadin Karakaya, Sandrine Tchatchou, Rongxi Yang, Petra Reinecke, Klaus Kühlcke, Brigitte Schlegelberger, Adrian J. Thrasher, Dieter Hoelzer, Reinhard Seger, Christof von Kalle, Manuel Grez
- Gene-modified autologous hematopoietic stem cells (HSC) can provide ample clinical benefits to subjects suffering from X-linked chronic granulomatous disease (X-CGD), a rare inherited immunodeficiency characterized by recurrent, often life-threatening bacterial and fungal infections. Here we report on the molecular and cellular events observed in two young adults with X-CGD treated by gene therapy in 2004. After the initial resolution of bacterial and fungal infections, both subjects showed silencing of transgene expression due to methylation of the viral promoter, and myelodysplasia with monosomy 7 as a result of insertional activation of ecotropic viral integration site 1 (EVI1). One subject died from overwhelming sepsis 27 months after gene therapy, whereas a second subject underwent an allogeneic HSC transplantation. Our data show that forced overexpression of EVI1 in human cells disrupts normal centrosome duplication, linking EVI1 activation to the development of genomic instability, monosomy 7 and clonal progression toward myelodysplasia.
MetadatenAuthor: | Stefan Stein, Marion Gabriele Ott, Stephan Schultze-StraßerORCiDGND, Anna Jauch, Barbara Burwinkel, Andrea Kinner, Manfred Schmidt, Alwin KrämerORCiDGND, Joachim SchwäbleGND, Hanno GlimmGND, Ulrike KöhlORCiDGND, Carolin Preiss, Claudia Ball, Hans MartinORCiD, Gudrun GöhringORCiDGND, Kerstin Schwarzwaelder, Wolf-Karsten Hofmann, Kadin Karakaya, Sandrine Tchatchou, Rongxi Yang, Petra Reinecke, Klaus Kühlcke, Brigitte Schlegelberger, Adrian J. Thrasher, Dieter HoelzerGND, Reinhard Seger, Christof von KalleORCiDGND, Manuel GrezGND |
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URN: | urn:nbn:de:hebis:30:3-337673 |
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DOI: | https://doi.org/10.1038/nm.2088 |
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ISSN: | 1078-8956 |
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ISSN: | 1546-170X |
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Pubmed Id: | https://pubmed.ncbi.nlm.nih.gov/20098431 |
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Parent Title (English): | Nature medicine |
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Publisher: | Nature Publ. Co. |
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Place of publication: | New York, NY |
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Document Type: | Article |
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Language: | English |
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Date of Publication (online): | 2014/05/14 |
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Year of first Publication: | 2010 |
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Publishing Institution: | Universitätsbibliothek Johann Christian Senckenberg |
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Release Date: | 2014/05/14 |
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Volume: | 16 |
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Issue: | 2 |
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Page Number: | 8 |
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First Page: | 198 |
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Last Page: | 204 |
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HeBIS-PPN: | 364931124 |
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Institutes: | Medizin / Medizin |
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| Angeschlossene und kooperierende Institutionen / Georg-Speyer-Haus |
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Dewey Decimal Classification: | 6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit |
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Sammlungen: | Universitätspublikationen |
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Licence (German): | Deutsches Urheberrecht |
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