Site- and allele-specific polycomb dysregulation in T-cell leukaemia

Jean-Marc Navarro, Aurore Touzart, Lydie C. Pradel, Marie Loosveld, Myriam Koubi, Romain Fenouil, Sandrine Le Noir, Muhammad Ahmad Maqbool, Ester Morgado, Claude Gregoire, Sebastien Jaeger, Emilie Mamessier, Charles Pignon, Salima Hacein-Bey-Abina, Bernard Malissen, Marta Gut, Ivo G. Gut, Hervé Dombret, Elizabeth A. Macintyre, Steven J. Howe, H. Bobby Gaspar, Adrian J. Thrasher, Norbert Ifrah, Dominique Payet-Bornet, Estelle Duprez, Jean-Christophe Andrau, Vahid Asnafi () and Bertrand Nadel ()
Additional contact information
Jean-Marc Navarro: Center of Immunology of Marseille Luminy, Aix-Marseille University, Parc Scientifique de Luminy case 906, 13288
Aurore Touzart: Université Paris Descartes Sorbonne Cité, Institut Necker-Enfants Malades (INEM), Institut national de recherche médicale (INSERM) U1151, and Laboratory of Onco-Hematology, Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Necker Enfants-Malades
Lydie C. Pradel: Center of Immunology of Marseille Luminy, Aix-Marseille University, Parc Scientifique de Luminy case 906, 13288
Marie Loosveld: Center of Immunology of Marseille Luminy, Aix-Marseille University, Parc Scientifique de Luminy case 906, 13288
Myriam Koubi: CRCM Inserm U1068, Institut Paoli Calmettes; Aix-Marseille Université, UM 105; CNRS UMR7258
Romain Fenouil: Center of Immunology of Marseille Luminy, Aix-Marseille University, Parc Scientifique de Luminy case 906, 13288
Sandrine Le Noir: Université Paris Descartes Sorbonne Cité, Institut Necker-Enfants Malades (INEM), Institut national de recherche médicale (INSERM) U1151, and Laboratory of Onco-Hematology, Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Necker Enfants-Malades
Muhammad Ahmad Maqbool: Center of Immunology of Marseille Luminy, Aix-Marseille University, Parc Scientifique de Luminy case 906, 13288
Ester Morgado: Center of Immunology of Marseille Luminy, Aix-Marseille University, Parc Scientifique de Luminy case 906, 13288
Claude Gregoire: Center of Immunology of Marseille Luminy, Aix-Marseille University, Parc Scientifique de Luminy case 906, 13288
Sebastien Jaeger: Center of Immunology of Marseille Luminy, Aix-Marseille University, Parc Scientifique de Luminy case 906, 13288
Emilie Mamessier: Center of Immunology of Marseille Luminy, Aix-Marseille University, Parc Scientifique de Luminy case 906, 13288
Charles Pignon: Center of Immunology of Marseille Luminy, Aix-Marseille University, Parc Scientifique de Luminy case 906, 13288
Salima Hacein-Bey-Abina: INSERM U429, Hôpital Necker-Enfants-Malades, 149 rue de Sèvres, 75015 Paris
Bernard Malissen: Center of Immunology of Marseille Luminy, Aix-Marseille University, Parc Scientifique de Luminy case 906, 13288
Marta Gut: Centro Nacional de Análisis Genómico
Ivo G. Gut: Centro Nacional de Análisis Genómico
Hervé Dombret: AP-HP Hôpital St-Louis
Elizabeth A. Macintyre: Université Paris Descartes Sorbonne Cité, Institut Necker-Enfants Malades (INEM), Institut national de recherche médicale (INSERM) U1151, and Laboratory of Onco-Hematology, Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Necker Enfants-Malades
Steven J. Howe: Centre for Immunodeficiency, Molecular and Cellular Immunology, Institute of Child Health, University College London
H. Bobby Gaspar: Centre for Immunodeficiency, Molecular and Cellular Immunology, Institute of Child Health, University College London
Adrian J. Thrasher: Centre for Immunodeficiency, Molecular and Cellular Immunology, Institute of Child Health, University College London
Norbert Ifrah: Services des Maladies du sang CHU and UMR Inserm U 892/CNRS 6299
Dominique Payet-Bornet: Center of Immunology of Marseille Luminy, Aix-Marseille University, Parc Scientifique de Luminy case 906, 13288
Estelle Duprez: Laboratoire Hématologie, APHM
Jean-Christophe Andrau: Center of Immunology of Marseille Luminy, Aix-Marseille University, Parc Scientifique de Luminy case 906, 13288
Vahid Asnafi: Université Paris Descartes Sorbonne Cité, Institut Necker-Enfants Malades (INEM), Institut national de recherche médicale (INSERM) U1151, and Laboratory of Onco-Hematology, Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Necker Enfants-Malades
Bertrand Nadel: Center of Immunology of Marseille Luminy, Aix-Marseille University, Parc Scientifique de Luminy case 906, 13288

Nature Communications, 2015, vol. 6, issue 1, 1-11

Abstract: Abstract T-cell acute lymphoblastic leukaemias (T-ALL) are aggressive malignant proliferations characterized by high relapse rates and great genetic heterogeneity. TAL1 is amongst the most frequently deregulated oncogenes. Yet, over half of the TAL1+ cases lack TAL1 lesions, suggesting unrecognized (epi)genetic deregulation mechanisms. Here we show that TAL1 is normally silenced in the T-cell lineage, and that the polycomb H3K27me3-repressive mark is focally diminished in TAL1+ T-ALLs. Sequencing reveals that >20% of monoallelic TAL1+ patients without previously known alterations display microinsertions or RAG1/2-mediated episomal reintegration in a single site 5′ to TAL1. Using ‘allelic-ChIP’ and CrispR assays, we demonstrate that such insertions induce a selective switch from H3K27me3 to H3K27ac at the inserted but not the germline allele. We also show that, despite a considerable mechanistic diversity, the mode of oncogenic TAL1 activation, rather than expression levels, impact on clinical outcome. Altogether, these studies establish site-specific epigenetic desilencing as a mechanism of oncogenic activation.

Date: 2015
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DOI: 10.1038/ncomms7094

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