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

作者：S. Hacein-Bey-Abina, Christof V. Kalle, Manfred Schmidt, Matthew Paul McCormack, Nicolas M Wulffraat, Philippe Leboulch, Apiradee Lim, Cameron S. Osborne, Robert Pawliuk, Estelle Morillon, Ricardo U. Sorensen, Alan Mark Forster, Peter Fraser, J. I. Cohen, Geneviève de Saint Basile, Ian E. Alexander, Uwe Wintergerst, Thierry Frébourg, Alain Aurias, Dominique Stoppa‐Lyonnet, Serge Pierrick Romana, I Radford-Weiss, Fabian Gross, Françoise Valensi, Éric Delabesse, Elizabeth A. Macintyre, F Sigaux, Jean Pierre Soulier, Lily E. Leiva, Manuela Wissler, Claudia Prinz, Terence Howard Rabbitts, Françoise Le Deist, Alain Fischer, Marina Cavazzana · 发表于：Science · 年份：2003 · DOI：10.1126/science.1088547 · 被引用次数：3603 · 研究领域：CAR-T cell therapy research、Virus-based gene therapy research、Immunodeficiency and Autoimmune Disorders

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 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.