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

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Hacein-Bey-Abina, S. | von Kalle, C. | Schmidt, M. | Mccormack, M. | Wulffraat, N. | Leboulch, P. | Lim, A. | Osborne, C. | Pawliuk, R. | Morillon, E. | Sorensen, R. | Forster, A. | Fraser, P. | Cohen, J. | de Saint Basile, G. | Alexander, I. | Wintergerst, U. | Frebourg, T. | Aurias, A. | Stoppa-Lyonnet, D. | Romana, S. | Radford-Weiss, I. | Gross, F. | Valensi, F. | Delabesse, Eric | Macintyre, E. | Sigaux, F. | Soulier, J. | Leiva, L. | Wissler, M. | Prinz, C. | Rabbitts, T. | Le Deist, F. | Fischer, A. | Cavazzana-Calvo, M.

Edité par CCSD ; American Association for the Advancement of Science (AAAS) -

International audience. 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.

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