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

• DOI: 10.1126/science.1088547
• Publication Date: 2003-10-16T21:09:09Z
• Authors: S. Hacein-Bey-Abina; C. Von Kalle; M. Schmidt; M. P. McCormack; N. Wulffraat; P. Leboulch; A. Lim; C. S. Osborne; R. Pawliuk; E. Morillon; R. Sorensen; A. Forster; P. Fraser; J. I. Cohen; G. de Saint Basile; I. Alexander; U. Wintergerst; T. Frebourg; A. Aurias; D. Stoppa-Lyonnet; S. Romana; I. Radford-Weiss; F. Gross; F. Valensi; E. Delabesse; E. Macintyre; F. Sigaux; J. Soulier; L. E. Leiva; M. Wissler; C. Prinz; T. H. Rabbitts; F. Le Deist; A. Fischer; M. Cavazzana-Calvo
• Keywords: Clinical Trials as Topic; 0303 health sciences; Genetic Vectors; Gene Transfer Techniques; Hematopoietic Stem Cell Transplantation; Infant; Genetic Therapy; LIM Domain Proteins; Hematopoietic Stem Cells; Proto-Oncogene Mas; Clone Cells; 3. Good health; DNA-Binding Proteins; Mutagenesis, Insertional; 03 medical and health sciences; Gene Expression Regulation; Proto-Oncogene Proteins; Metalloproteins; Proto-Oncogenes; Humans; Leukemia-Lymphoma, Adult T-Cell; Promoter Regions, Genetic; Adaptor Proteins, Signal Transducing

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