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...

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Hauptverfasser: Stein, Stefan (VerfasserIn) , Ott, Marion G. (VerfasserIn) , Schultze-Straßer, Stephan (VerfasserIn) , Jauch, Anna (VerfasserIn) , Burwinkel, Barbara (VerfasserIn) , Kinner, Andrea (VerfasserIn) , Schmidt, Manfred (VerfasserIn) , Krämer, Alwin (VerfasserIn) , Schwäble, Joachim (VerfasserIn) , Glimm, Hanno (VerfasserIn) , Köhl, Ulrike (VerfasserIn) , Preiss, Carolin (VerfasserIn) , Ball, Claudia R. (VerfasserIn) , Martin, Hans (VerfasserIn) , Göhring, Gudrun (VerfasserIn) , Schwarzwälder, Kerstin (VerfasserIn) , Hofmann, Wolf-Karsten (VerfasserIn) , Karakaya, Kadin (VerfasserIn) , Tchatchou, Sandrine (VerfasserIn) , Yang, Rongxi (VerfasserIn) , Reinecke, Petra (VerfasserIn) , Kühlcke, Klaus (VerfasserIn) , Schlegelberger, Brigitte (VerfasserIn) , Thrasher, Adrian J. (VerfasserIn) , Hoelzer, Dieter (VerfasserIn) , Seger, Reinhard (VerfasserIn) , Kalle, Christof von (VerfasserIn) , Grez, Manuel (VerfasserIn)
Dokumenttyp: Article (Journal)
Sprache:Englisch
Veröffentlicht: 24 January 2010
In: Nature medicine
Year: 2010, Jahrgang: 16, Heft: 2, Pages: 198-204
ISSN:1546-170X
Online-Zugang: Volltext
Verfasserangaben:Stefan Stein, Marion G. Ott, Stephan Schultze-Strasser, Anna Jauch, Barbara Burwinkel, Andrea Kinner, Manfred Schmidt, Alwin Krämer, Joachim Schwäble, Hanno Glimm, Ulrike Koehl, 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

MARC

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520 |a 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. 
650 4 |a Adult 
650 4 |a Chromosomes, Human, Pair 7 
650 4 |a DNA-Binding Proteins 
650 4 |a Genetic Therapy 
650 4 |a Genomic Instability 
650 4 |a Granulomatous Disease, Chronic 
650 4 |a Humans 
650 4 |a MDS1 and EVI1 Complex Locus Protein 
650 4 |a Monosomy 
650 4 |a Myelodysplastic Syndromes 
650 4 |a NADPH Oxidases 
650 4 |a Promoter Regions, Genetic 
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