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LMO2-Associated Clonal T Cell Proliferation in Two Patients after Gene Therapy for SCID-X1
S. Hacein-Bey-Abina,1,2*C. Von Kalle,6,7,8M. Schmidt,6,7M. P. McCormack,9N. Wulffraat,10P. Leboulch,11A. Lim,12C. S. Osborne,13R. Pawliuk,11E. Morillon,2R. Sorensen,19A. Forster,9P. Fraser,13J. I. Cohen,15G. de Saint Basile,1I. Alexander,16U. Wintergerst,17T. Frebourg,18A. Aurias,19D. Stoppa-Lyonnet,20S. Romana,3I. Radford-Weiss,3F. Gross,2F. Valensi,4E. Delabesse,4E. Macintyre,4F. Sigaux,20J. Soulier,21L. E. Leiva,14M. Wissler,6,7C. Prinz,6,7T. H. Rabbitts,9F. Le Deist,1A. Fischer,1,5M. Cavazzana-Calvo1,2
We have previously shown correction of X-linked severe combinedimmunodeficiency [SCID-X1, also known as chain (c) deficiency]in 9 out of 10 patients by retrovirus-mediated c gene transferinto autologous CD34 bone marrow cells. However, almost 3 yearsafter gene therapy, uncontrolled exponential clonal proliferationof mature T cells (with + or ß+ T cell receptors)has occurred in the two youngest patients. Both patients' clonesshowed retrovirus vector integration in proximity to the LMO2proto-oncogene promoter, leading to aberrant transcription andexpression of LMO2. Thus, retrovirus vector insertion can triggerderegulated premalignant cell proliferation with unexpectedfrequency, most likely driven by retrovirus enhancer activityon the LMO2 gene promoter.
1 INSERM Unit 429, Cedex 15, France. 2 Department de Biotherapie Assistance Publique–Hopitaux de Paris, Cedex 15, France. 3 Laboratoire de Cytogénétique, Cedex 15, France. 4 Laboratoire Central d'Hématologie and CNRS Unité de Recherche Associée 1461, Université Paris V, Cedex 15, France. 5 Unité d'Immunologie et d'Hématologie Pédiatriques, Hôpital Necker, 75743 Paris, Cedex 15, France. 6 Department of Internal Medicine, University of Freiburg, Freiburg, Germany. 7 Institute of Molecular Medicine and Cell Research, University of Freiburg, Freiburg, Germany. 8 Children's Hospital Research Foundation, Cincinnati, OH, USA. 9 Medical Research Council, Laboratory of Molecular Biology, Hills Road, Cambridge CB2 2QH, UK. 10 University Medical Center Utrecht–Wilhelmina Kinderziekenhuis, Utrecht, Netherlands. 11 Harvard Medical School and Genetics Division, Brigham and Women's Hospital, Boston, MA 02115, USA. 12 INSERM Unit 277, Institut Pasteur, 75730 Paris, France. 13 Laboratory of Chromatin and Gene Expression, Developmental Genetics Programme, The Babraham Institute, Cambridge CB2 4AT, UK. 14 Department of Pediatrics, Louisiana State University Health Sciences Center and Children's Hospital, New Orleans, LA 70112, USA 15 Medical Virology Section, Laboratory of Clinical Investigation, National Institute of Allergy and Infectious Diseases, Bethesda, MD 20892, USA. 16 The Children's Hospital at Westmead, Sydney, NSW 2145, Australia. 17 University and Children's Hospital, Lindwurmstraße 4, 80337 Munich, Germany. 18 Service de Genetique, Centre Hospitalo-Universitaire et Equipte Mixte INSERM 9906, Faculté de Médecine et de Pharmacie, 76183 Rouen, France. 19 INSERM Unit 434, Institut Curie, Paris, Cedex 15, France. 20 Department of Oncology Genetics, Institut Curie, Paris, Cedex 15, France. 21 INSERM Unit 462, Hôpital Saint Louis, Paris, France.
* These authors contributed equally to this work.
These authors contributed equally to this work.
To whom correspondence should be addressed. E-mail: fischer{at}necker.fr
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chain (
+ or 
ß+ T cell receptors) has occurred in the two youngest patients. Both patients' clones showed retrovirus vector integration in proximity to the LMO2 proto-oncogene promoter, leading to aberrant transcription and expression of LMO2. Thus, retrovirus vector insertion can trigger deregulated premalignant cell proliferation with unexpected frequency, most likely driven by retrovirus enhancer activity on the LMO2 gene promoter. 
These authors contributed equally to this work. 
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