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Science 17 October 2003:
Vol. 302. no. 5644, pp. 415 - 419
DOI: 10.1126/science.1088547

Research Articles

LMO2-Associated Clonal T Cell Proliferation in Two Patients after Gene Therapy for SCID-X1

S. Hacein-Bey-Abina,1,2* C. Von Kalle,6,7,8 M. Schmidt,6,7 M. P. McCormack,9 N. Wulffraat,10 P. Leboulch,11 A. Lim,12 C. S. Osborne,13 R. Pawliuk,11 E. Morillon,2 R. Sorensen,19 A. Forster,9 P. Fraser,13 J. I. Cohen,15 G. de Saint Basile,1 I. Alexander,16 U. Wintergerst,17 T. Frebourg,18 A. Aurias,19 D. Stoppa-Lyonnet,20 S. Romana,3 I. Radford-Weiss,3 F. Gross,2 F. Valensi,4 E. Delabesse,4 E. Macintyre,4 F. Sigaux,20 J. Soulier,21 L. E. Leiva,14 M. Wissler,6,7 C. Prinz,6,7 T. H. Rabbitts,9 F. Le Deist,1 A. Fischer,1,5{dagger}{ddagger} M. Cavazzana-Calvo1,2{dagger}

We have previously shown correction of X-linked severe combined immunodeficiency [SCID-X1, also known as {gamma} chain ({gamma}c) deficiency] in 9 out of 10 patients by retrovirus-mediated {gamma}c gene transfer into autologous CD34 bone marrow cells. However, almost 3 years after gene therapy, uncontrolled exponential clonal proliferation of mature T cells (with {gamma}{delta}+ or {alpha}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.

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.

{dagger} These authors contributed equally to this work.

{ddagger} To whom correspondence should be addressed. E-mail: fischer{at}necker.fr

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Altruistic donor T cells.
P. Tiberghien (2007)
Blood 109, 4595
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The C-terminal loop of the homing endonuclease I-CreI is essential for site recognition, DNA binding and cleavage.
J. Prieto, P. Redondo, D. Padro, S. Arnould, J.-C. Epinat, F. Paques, F. J. Blanco, and G. Montoya (2007)
Nucleic Acids Res. 35, 3262-3271
   Abstract »    Full Text »    PDF »
Single-stranded DNA-binding proteins regulate the abundance of LIM domain and LIM domain-binding proteins.
Z. Xu, X. Meng, Y. Cai, H. Liang, L. Nagarajan, and S. J. Brandt (2007)
Genes & Dev. 21, 942-955
   Abstract »    Full Text »    PDF »
Diamond-Blackfan anemia: erythropoiesis lost in translation.
J. Flygare and S. Karlsson (2007)
Blood 109, 3152-3154
   Abstract »    Full Text »    PDF »
Clinical trials with adult stem/progenitor cells for tissue repair: let's not overlook some essential precautions.
D. J. Prockop and S. D. Olson (2007)
Blood 109, 3147-3151
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Gene Therapy in the Treatment of Heart Failure.
H. Ly, Y. Kawase, R. Yoneyama, and R. J. Hajjar (2007)
Physiology 22, 81-96
   Abstract »    Full Text »    PDF »
Site-directed transposon integration in human cells.
S. R. Yant, Y. Huang, B. Akache, and M. A. Kay (2007)
Nucleic Acids Res. 35, e50
   Abstract »    Full Text »    PDF »
Retroviral insertional mutagenesis identifies RUNX genes involved in chronic myeloid leukemia disease persistence under imatinib treatment.
C. Miething, R. Grundler, C. Mugler, S. Brero, J. Hoepfl, J. Geigl, M. R. Speicher, O. Ottmann, C. Peschel, and J. Duyster (2007)
PNAS 104, 4594-4599
   Abstract »    Full Text »    PDF »
Chimeric T-cell receptors: new challenges for targeted immunotherapy in hematologic malignancies.
E. Biagi, V. Marin, G. M. P. Giordano Attianese, E. Dander, G. D'Amico, and A. Biondi (2007)
Haematologica 92, 381-388
   Abstract »    Full Text »    PDF »
Retroviral vector insertion sites associated with dominant hematopoietic clones mark "stemness" pathways.
O. S. Kustikova, H. Geiger, Z. Li, M. H. Brugman, S. M. Chambers, C. A. Shaw, K. Pike-Overzet, D. d. Ridder, F. J. T. Staal, G. v. Keudell, et al. (2007)
Blood 109, 1897-1907
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The oncoprotein LMO2 is expressed in normal germinal-center B cells and in human B-cell lymphomas.
Y. Natkunam, S. Zhao, D. Y. Mason, J. Chen, B. Taidi, M. Jones, A. S. Hammer, S. Hamilton Dutoit, I. S. Lossos, and R. Levy (2007)
Blood 109, 1636-1642
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Cyclophilin A, TRIM5, and Resistance to Human Immunodeficiency Virus Type 1 Infection.
J. Luban (2007)
J. Virol. 81, 1054-1061
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Importance of Receptor Usage, Fli1 Activation, and Mouse Strain for the Stem Cell Specificity of 10A1 Murine Leukemia Virus Leukemogenicity.
M. Rodenburg, M. Fischer, A. Engelmann, S. O. Harbers, M. Ziegler, J. Lohler, and C. Stocking (2007)
J. Virol. 81, 732-742
   Abstract »    Full Text »    PDF »
Molecular basis of hematology.
M. P. Mims and J. T. Prchal (2007)
ASH Self-Assessment Program 2007, 1-22
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The Yin and Yang of Stem Cell Gene Therapy: Insights into Hematopoiesis, Leukemogenesis, and Gene Therapy Safety.
C. E. Dunbar (2007)
Hematology 2007, 460-465
   Abstract »    Full Text »    PDF »
A combinatorial approach to create artificial homing endonucleases cleaving chosen sequences.
J. Smith, S. Grizot, S. Arnould, A. Duclert, J.-C. Epinat, P. Chames, J. Prieto, P. Redondo, F. J. Blanco, J. Bravo, et al. (2006)
Nucleic Acids Res. 34, e149
   Abstract »    Full Text »    PDF »
Cellular delivery of small interfering RNA by a non-covalently attached cell-penetrating peptide: quantitative analysis of uptake and biological effect.
S. Veldhoen, S. D. Laufer, A. Trampe, and T. Restle (2006)
Nucleic Acids Res. 34, 6561-6573
   Abstract »    Full Text »    PDF »



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