title: Genomic instability and myelodysplasia with monosomy 7 consequent to EVI1 activation after gene therapy for chronic granulomatous disease.
abstract: 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.
authors.affiliation: Institute for Biomedical Research, Georg-Speyer-Haus, Frankfurt, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Stein
authors.forename: Marion G
authors.initials: MG
authors.lastname: Ott
authors.forename: Stephan
authors.initials: S
authors.lastname: Schultze-Strasser
authors.forename: Anna
authors.initials: A
authors.lastname: Jauch
authors.forename: Barbara
authors.initials: B
authors.lastname: Burwinkel
authors.forename: Andrea
authors.initials: A
authors.lastname: Kinner
authors.forename: Manfred
authors.initials: M
authors.lastname: Schmidt
authors.forename: Alwin
authors.initials: A
authors.lastname: Krämer
authors.forename: Joachim
authors.initials: J
authors.lastname: Schwäble
authors.forename: Hanno
authors.initials: H
authors.lastname: Glimm
authors.forename: Ulrike
authors.initials: U
authors.lastname: Koehl
authors.forename: Carolin
authors.initials: C
authors.lastname: Preiss
authors.forename: Claudia
authors.initials: C
authors.lastname: Ball
authors.forename: Hans
authors.initials: H
authors.lastname: Martin
authors.forename: Gudrun
authors.initials: G
authors.lastname: Göhring
authors.forename: Kerstin
authors.initials: K
authors.lastname: Schwarzwaelder
authors.forename: Wolf-Karsten
authors.initials: WK
authors.lastname: Hofmann
authors.forename: Kadin
authors.initials: K
authors.lastname: Karakaya
authors.forename: Sandrine
authors.initials: S
authors.lastname: Tchatchou
authors.forename: Rongxi
authors.initials: R
authors.lastname: Yang
authors.forename: Petra
authors.initials: P
authors.lastname: Reinecke
authors.forename: Klaus
authors.initials: K
authors.lastname: Kühlcke
authors.forename: Brigitte
authors.initials: B
authors.lastname: Schlegelberger
authors.forename: Adrian J
authors.initials: AJ
authors.lastname: Thrasher
authors.forename: Dieter
authors.initials: D
authors.lastname: Hoelzer
authors.forename: Reinhard
authors.initials: R
authors.lastname: Seger
authors.forename: Christof
authors.initials: C
authors.lastname: von Kalle
authors.forename: Manuel
authors.initials: M
authors.lastname: Grez
mesh_terms: D000328:Adult; D002897:Chromosomes, Human, Pair 7; D004268:DNA-Binding Proteins / Q000235:genetics*; D015316:Genetic Therapy; D042822:Genomic Instability; D006105:Granulomatous Disease, Chronic / Q000628:therapy*; D006801:Humans; D000074008:MDS1 and EVI1 Complex Locus Protein; D009006:Monosomy; D009190:Myelodysplastic Syndromes / Q000235:genetics*; D019255:NADPH Oxidases / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011519:Proto-Oncogenes / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics*
chemical_list: D004268:DNA-Binding Proteins; D000074008:MDS1 and EVI1 Complex Locus Protein; C063575:MECOM protein, human; D014157:Transcription Factors; D019255:NADPH Oxidases