Genomic Instability and Myelodysplasia with Monosomy 7 Consequent to EVI1 Activation After Gene Therapy for Chronic Granulomatous Disease

Overview

Journal Nat Med

Specialties General Medicine
Molecular Biology

Date 2010 Jan 26

PMID 20098431

Citations 382

Authors

Stefan Stein

Marion G Ott

Stephan Schultze-Strasser

Anna Jauch

Barbara Burwinkel

Andrea Kinner

Manfred Schmidt

Alwin Kramer

Joachim Schwable

Hanno Glimm

Ulrike Koehl

Carolin Preiss

Claudia Ball

Hans Martin

Gudrun Gohring

Kerstin Schwarzwaelder

Wolf-Karsten Hofmann

Kadin Karakaya

Sandrine Tchatchou

Rongxi Yang

Petra Reinecke

Klaus Kuhlcke

Brigitte Schlegelberger

Adrian J Thrasher

Dieter Hoelzer

Reinhard Seger

Christof von Kalle

Manuel Grez

Affiliations

Soon will be listed here.

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.

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