LMO2 -Associated Clonal T Cell Proliferation in Two Patients after Gene Therapy for SCID-X1
2003; American Association for the Advancement of Science; Volume: 302; Issue: 5644 Linguagem: Inglês
10.1126/science.1088547
ISSN1095-9203
AutoresS. Hacein-Bey-Abina, Christof von Kalle, Manfred Schmidt, Matthew P. McCormack, N. M. Wulffraat, Philippe Leboulch, Apiradee Lim, Cameron S. Osborne, Robert Pawliuk, Estelle Morillon, Ricardo U. Sorensen, A. Förster, Peter Fraser, J. I. Cohen, Geneviève de Saint Basile, Ian E. Alexander, Uwe Wintergerst, Thierry Frébourg, Alain Aurias, Dominique Stoppa‐Lyonnet, Serge Romana, I Radford-Weiss, Fabian Gross, F Valensi, Éric Delabesse, Elizabeth Macintyre, F Sigaux, Jean Soulier, Lily E. Leiva, Manuela Wissler, Claudia Prinz, Terence H. Rabbitts, Françoise Le Deist, Alain Fischer, Marina Cavazzana,
Tópico(s)Immunodeficiency and Autoimmune Disorders
ResumoWe 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 gammadelta+ or alphabeta+ 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.
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