%0 Journal Article %T Transfusion independence and HMGA2 activation after gene therapy of human β-thalassaemia %+ Developpement Normal et Pathologique du Système Immunitaire %+ Clinical Investigation Center in Biotherapy %+ Institut des Maladies Emergentes et des Thérapies Innovantes (IMETI) %+ Thérapie génique et contrôle de l'expansion cellulaire (UMR E007) %+ Genetix-France %+ Department of Microbiology %+ Genetix Pharmaceuticals %+ Genetics Division, Boston %+ Department of Life Sciences, Trieste %+ Service d'hématologie pédiatrique %+ CHU Tenon [AP-HP] %+ Department of Medicine and Department of Genetics and Development %+ Departments of Hematology %+ Institute of Hematology %+ Service d'hématologie greffe [Saint-Louis] %+ Genetique et Biotherapies des Maladies Degeneratives et Proliferatives du Systeme Nerveux (Inserm U745) %+ Department of Medical and Molecular Genetics %+ Institut Mondor de Recherche Biomédicale (IMRB) %A Cavazzana-Calvo, Marina %A Payen, Emmanuel %A Negre, Olivier %A Wang, Gary %A Hehir, Kathleen %A Fusil, Floriane %A Down, Julian %A Denaro, Maria %A Brady, Troy %A Westerman, Karen %A Cavallesco, Resy %A Gillet-Legrand, Beatrix %A Caccavelli, Laure %A Sgarra, Riccardo %A Maouche-Chrétien, Leila %A Bernaudin, Françoise %A Girot, Robert %A Dorazio, Ronald %A Mulder, Geert-Jan %A Polack, Axel %A Bank, Arthur %A Soulier, Jean %A Larghero, Jérôme %A Kabbara, Nabil %A Dalle, Bruno %A Gourmel, Bernard %A Socie, Gérard %A Chrétien, Stany %A Cartier, Nathalie %A Aubourg, Patrick %A Fischer, Alain %A Cornetta, Kenneth %A Galacteros, Frédéric %A Beuzard, Yves %A Gluckman, Eliane %A Bushman, Frederick %A Hacein-Bey-Abina, Salima %A Leboulch, Philippe %< avec comité de lecture %@ 0028-0836 %J Nature %I Nature Publishing Group %V 467 %N 7313 %P 318-322 %8 2010 %D 2010 %R 10.1038/nature09328 %Z Life Sciences [q-bio]/Cellular BiologyJournal articles %X The β-haemoglobinopathies are the most prevalent inherited disorders worldwide. Gene therapy of β-thalassaemia is particularly challenging given the requirement for massive haemoglobin production in a lineage-specific manner and the lack of selective advantage for corrected haematopoietic stem cells. Compound β$^E$/β$^0$-thalassaemia is the most common form of severe thalassaemia in southeast Asian countries and their diasporas1, 2. The β$^E$-globin allele bears a point mutation that causes alternative splicing. The abnormally spliced form is non-coding, whereas the correctly spliced messenger RNA expresses a mutated β$^E$-globin with partial instability. When this is compounded with a non-functional β$^0$ allele, a profound decrease in β-globin synthesis results, and approximately half of β$^E$/β$^0$-thalassaemia patients are transfusion-dependent. The only available curative therapy is allogeneic haematopoietic stem cell transplantation, although most patients do not have a human-leukocyte-antigen-matched, geno-identical donor, and those who do still risk rejection or graft-versus-host disease. Here we show that, 33 months after lentiviral β-globin gene transfer, an adult patient with severe β$^E$/β$^0$-thalassaemia dependent on monthly transfusions since early childhood has become transfusion independent for the past 21 months. Blood haemoglobin is maintained between 9 and 10 g dl$^{−1}$, of which one-third contains vector-encoded β-globin. Most of the therapeutic benefit results from a dominant, myeloid-biased cell clone, in which the integrated vector causes transcriptional activation of $HMGA2$ in erythroid cells with further increased expression of a truncated $HMGA2$ mRNA insensitive to degradation by let-7 microRNAs. The clonal dominance that accompanies therapeutic efficacy may be coincidental and stochastic or result from a hitherto benign cell expansion caused by dysregulation of the $HMGA2$ gene in stem/progenitor cells %G English %L cea-00905288 %U https://cea.hal.science/cea-00905288 %~ CEA %~ UNIV-PARIS5 %~ UNIV-PARIS7 %~ ENSCP %~ CNRS %~ ENSC-PARIS %~ IFR71 %~ APHP %~ PARISTECH %~ IMRB %~ UPEC %~ PSL %~ JACOB %~ CEA-DRF %~ SORBONNE-UNIVERSITE %~ SU-INF-2018 %~ SU-MEDECINE %~ SU-MED %~ UNIV-PARIS %~ ENSCP-PSL %~ SU-TI %~ ALLIANCE-SU