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

• Published in: Nature medicine Vol. 16; no. 2; pp. 198 - 204
• Main Authors: Stein, Stefan, Ott, Marion G, Schultze-Strasser, Stephan, Jauch, Anna, Burwinkel, Barbara, Kinner, Andrea, Schmidt, Manfred, Krämer, Alwin, Schwäble, Joachim, Glimm, Hanno, Koehl, Ulrike, Preiss, Carolin, Ball, Claudia, Martin, Hans, Göhring, Gudrun, Schwarzwaelder, Kerstin, Hofmann, Wolf-Karsten, Karakaya, Kadin, Tchatchou, Sandrine, Yang, Rongxi, Reinecke, Petra, Kühlcke, Klaus, Schlegelberger, Brigitte, Thrasher, Adrian J, Hoelzer, Dieter, Seger, Reinhard, von Kalle, Christof, Grez, Manuel
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.02.2010; Nature Publishing Group
• Subjects: 631/208/737/211; 692/699/1541; 692/699/249/1570; 692/700/565/201; Adult; Biomedical and Life Sciences; Biomedical research; Biomedicine; Cancer Research; Care and treatment; Chromosomes, Human, Pair 7; Chronic granulomatous disease; Development and progression; DNA-Binding Proteins - genetics; Gene expression; Gene therapy; Genetic aspects; Genetic disorders; Genetic Therapy; Genomic Instability; Genomics; Granulomatous Disease, Chronic - therapy; Health aspects; Humans; Immune system; Infectious Diseases; MDS1 and EVI1 Complex Locus Protein; Metabolic Diseases; Methylation; Molecular Medicine; Monosomy; Myelodysplastic syndromes; Myelodysplastic Syndromes - genetics; NADPH Oxidases - metabolism; Neurosciences; Promoter Regions, Genetic; Proto-Oncogenes - genetics; Risk factors; Stem cells; Transcription Factors - genetics; Young adults; Germany
• ISSN: 1078-8956; 1546-170X; 1546-170X
• DOI: 10.1038/nm.2088

Transduced hematopoietic stem cells can benefit patients with X-linked chronic granulomatous disease (a genetic immunodeficiency), but it's not risk free. In two treated patients, insertional activation of MDS1 – EVI1 , PRDM16 and SETBP1 markedly increased the number of transduced cells in the blood, leading to oligoclonal hematopoiesis, monosomy 7 and a myelodysplastic syndrome ( pages 163–165 ). 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.