TY - JOUR A1 - Stein, Stefan A1 - Ott, Marion Gabriele A1 - Schultze-Straßer, Stephan A1 - Jauch, Anna A1 - Burwinkel, Barbara A1 - Kinner, Andrea A1 - Schmidt, Manfred A1 - Krämer, Alwin A1 - Schwäble, Joachim A1 - Glimm, Hanno A1 - Köhl, Ulrike A1 - Preiss, Carolin A1 - Ball, Claudia A1 - Martin, Hans A1 - Göhring, Gudrun A1 - Schwarzwaelder, Kerstin A1 - Hofmann, Wolf-Karsten A1 - Karakaya, Kadin A1 - Tchatchou, Sandrine A1 - Yang, Rongxi A1 - Reinecke, Petra A1 - Kühlcke, Klaus A1 - Schlegelberger, Brigitte A1 - Thrasher, Adrian J. A1 - Hoelzer, Dieter A1 - Seger, Reinhard A1 - Kalle, Christof von A1 - Grez, Manuel T1 - Genomic instability and myelodysplasia with monosomy 7 consequent to EVI1 activation after gene therapy for chronic granulomatous disease T2 - Nature medicine N2 - 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. Y1 - 2014 UR - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/33767 UR - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-337673 SN - 1078-8956 SN - 1546-170X VL - 16 IS - 2 SP - 198 EP - 204 PB - Nature Publ. Co. CY - New York, NY ER -