Genomic instability and myelodysplasia with monosomy 7 consequent to EVI1 activation after gene therapy for chronic granulomatous disease

  • 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.

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Author:Stefan Stein, Marion Gabriele Ott, Stephan Schultze-Straßer, Anna Jauch, Barbara Burwinkel, Andrea Kinner, Manfred Schmidt, Alwin KrämerGND, Joachim Schwäble, Hanno Glimm, Ulrike Köhl, 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 Kalle, Manuel Grez
URN:urn:nbn:de:hebis:30:3-337673
DOI:https://doi.org/10.1038/nm.2088
ISSN:1078-8956
ISSN:1546-170X
Pubmed Id:https://pubmed.ncbi.nlm.nih.gov/20098431
Parent Title (English):Nature medicine
Publisher:Nature Publ. Co.
Place of publication:New York, NY
Document Type:Article
Language:English
Date of Publication (online):2014/05/14
Year of first Publication:2010
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2014/05/14
Volume:16
Issue:2
Page Number:8
First Page:198
Last Page:204
HeBIS-PPN:364931124
Institutes:Medizin / Medizin
Angeschlossene und kooperierende Institutionen / Georg-Speyer-Haus
Dewey Decimal Classification:6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Sammlungen:Universitätspublikationen
Licence (German):License LogoDeutsches Urheberrecht