title: Site- and allele-specific polycomb dysregulation in T-cell leukaemia.
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.
authors.affiliation: 1] Center of Immunology of Marseille Luminy, Aix-Marseille University, Parc Scientifique de Luminy case 906, 13288 Marseille, France [2] INSERM U1104, 13288 Marseille, France [3] CNRS UMR7280, 13288 Marseille, France.
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Navarro
authors.affiliation: 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, 75015 Paris, France.
authors.forename: Aurore
authors.initials: A
authors.lastname: Touzart
authors.affiliation: 1] Center of Immunology of Marseille Luminy, Aix-Marseille University, Parc Scientifique de Luminy case 906, 13288 Marseille, France [2] INSERM U1104, 13288 Marseille, France [3] CNRS UMR7280, 13288 Marseille, France.
authors.forename: Lydie C
authors.initials: LC
authors.lastname: Pradel
authors.affiliation: 1] Center of Immunology of Marseille Luminy, Aix-Marseille University, Parc Scientifique de Luminy case 906, 13288 Marseille, France [2] INSERM U1104, 13288 Marseille, France [3] CNRS UMR7280, 13288 Marseille, France [4] Laboratoire Hématologie, APHM, 13385 Marseille, France.
authors.forename: Marie
authors.initials: M
authors.lastname: Loosveld
authors.affiliation: CRCM Inserm U1068, Institut Paoli Calmettes; Aix-Marseille Université, UM 105; CNRS UMR7258, 13009 Marseille, France.
authors.forename: Myriam
authors.initials: M
authors.lastname: Koubi
authors.affiliation: 1] Center of Immunology of Marseille Luminy, Aix-Marseille University, Parc Scientifique de Luminy case 906, 13288 Marseille, France [2] INSERM U1104, 13288 Marseille, France [3] CNRS UMR7280, 13288 Marseille, France.
authors.forename: Romain
authors.initials: R
authors.lastname: Fenouil
authors.affiliation: 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, 75015 Paris, France.
authors.forename: Sandrine
authors.initials: S
authors.lastname: Le Noir
authors.affiliation: 1] Center of Immunology of Marseille Luminy, Aix-Marseille University, Parc Scientifique de Luminy case 906, 13288 Marseille, France [2] INSERM U1104, 13288 Marseille, France [3] CNRS UMR7280, 13288 Marseille, France.
authors.forename: Muhammad Ahmad
authors.initials: MA
authors.lastname: Maqbool
authors.affiliation: 1] Center of Immunology of Marseille Luminy, Aix-Marseille University, Parc Scientifique de Luminy case 906, 13288 Marseille, France [2] INSERM U1104, 13288 Marseille, France [3] CNRS UMR7280, 13288 Marseille, France.
authors.forename: Ester
authors.initials: E
authors.lastname: Morgado
authors.affiliation: 1] Center of Immunology of Marseille Luminy, Aix-Marseille University, Parc Scientifique de Luminy case 906, 13288 Marseille, France [2] INSERM U1104, 13288 Marseille, France [3] CNRS UMR7280, 13288 Marseille, France.
authors.forename: Claude
authors.initials: C
authors.lastname: Gregoire
authors.affiliation: 1] Center of Immunology of Marseille Luminy, Aix-Marseille University, Parc Scientifique de Luminy case 906, 13288 Marseille, France [2] INSERM U1104, 13288 Marseille, France [3] CNRS UMR7280, 13288 Marseille, France.
authors.forename: Sebastien
authors.initials: S
authors.lastname: Jaeger
authors.affiliation: 1] Center of Immunology of Marseille Luminy, Aix-Marseille University, Parc Scientifique de Luminy case 906, 13288 Marseille, France [2] INSERM U1104, 13288 Marseille, France [3] CNRS UMR7280, 13288 Marseille, France.
authors.forename: Emilie
authors.initials: E
authors.lastname: Mamessier
authors.affiliation: 1] Center of Immunology of Marseille Luminy, Aix-Marseille University, Parc Scientifique de Luminy case 906, 13288 Marseille, France [2] INSERM U1104, 13288 Marseille, France [3] CNRS UMR7280, 13288 Marseille, France.
authors.forename: Charles
authors.initials: C
authors.lastname: Pignon
authors.affiliation: Biotherapy Department, INSERM U429, Hôpital Necker-Enfants-Malades, 149 rue de Sèvres, 75015 Paris, France.
authors.forename: Salima
authors.initials: S
authors.lastname: Hacein-Bey-Abina
authors.affiliation: 1] Center of Immunology of Marseille Luminy, Aix-Marseille University, Parc Scientifique de Luminy case 906, 13288 Marseille, France [2] INSERM U1104, 13288 Marseille, France [3] CNRS UMR7280, 13288 Marseille, France.
authors.forename: Bernard
authors.initials: B
authors.lastname: Malissen
authors.affiliation: Centro Nacional de Análisis Genómico, 08028 Barcelona, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Gut
authors.affiliation: Centro Nacional de Análisis Genómico, 08028 Barcelona, Spain.
authors.forename: Ivo G
authors.initials: IG
authors.lastname: Gut
authors.affiliation: Department of Hematology, AP-HP Hôpital St-Louis, 75010 Paris, France.
authors.forename: Hervé
authors.initials: H
authors.lastname: Dombret
authors.affiliation: 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, 75015 Paris, France.
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Macintyre
authors.affiliation: Centre for Immunodeficiency, Molecular and Cellular Immunology, Institute of Child Health, University College London, London WC1N 1EH, UK.
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Howe
authors.affiliation: Centre for Immunodeficiency, Molecular and Cellular Immunology, Institute of Child Health, University College London, London WC1N 1EH, UK.
authors.forename: H Bobby
authors.initials: HB
authors.lastname: Gaspar
authors.affiliation: Centre for Immunodeficiency, Molecular and Cellular Immunology, Institute of Child Health, University College London, London WC1N 1EH, UK.
authors.forename: Adrian J
authors.initials: AJ
authors.lastname: Thrasher
authors.affiliation: Services des Maladies du sang CHU and UMR Inserm U 892/CNRS 6299, 49933 Angers, France.
authors.forename: Norbert
authors.initials: N
authors.lastname: Ifrah
authors.affiliation: 1] Center of Immunology of Marseille Luminy, Aix-Marseille University, Parc Scientifique de Luminy case 906, 13288 Marseille, France [2] INSERM U1104, 13288 Marseille, France [3] CNRS UMR7280, 13288 Marseille, France.
authors.forename: Dominique
authors.initials: D
authors.lastname: Payet-Bornet
authors.affiliation: Laboratoire Hématologie, APHM, 13385 Marseille, France.
authors.forename: Estelle
authors.initials: E
authors.lastname: Duprez
authors.affiliation: 1] Center of Immunology of Marseille Luminy, Aix-Marseille University, Parc Scientifique de Luminy case 906, 13288 Marseille, France [2] INSERM U1104, 13288 Marseille, France [3] CNRS UMR7280, 13288 Marseille, France.
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Andrau
authors.affiliation: 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, 75015 Paris, France.
authors.forename: Vahid
authors.initials: V
authors.lastname: Asnafi
authors.affiliation: 1] Center of Immunology of Marseille Luminy, Aix-Marseille University, Parc Scientifique de Luminy case 906, 13288 Marseille, France [2] INSERM U1104, 13288 Marseille, France [3] CNRS UMR7280, 13288 Marseille, France.
authors.forename: Bertrand
authors.initials: B
authors.lastname: Nadel
mesh_terms: D000107:Acetylation; D000328:Adult; D000483:Alleles; D001483:Base Sequence; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D047369:Chromatin Immunoprecipitation; D004268:DNA-Binding Proteins / Q000378:metabolism; D044127:Epigenesis, Genetic; D015973:Gene Expression Regulation, Leukemic; D056426:Genetic Loci; D006657:Histones / Q000378:metabolism; D018398:Homeodomain Proteins / Q000378:metabolism; D006801:Humans; D019169:Jurkat Cells; D008745:Methylation; D008969:Molecular Sequence Data; D016254:Mutagenesis, Insertional; D009687:Nuclear Proteins / Q000378:metabolism; D010957:Plasmids / Q000235:genetics; D063146:Polycomb-Group Proteins / Q000235:genetics* / Q000378:metabolism; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics*; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D016019:Survival Analysis; D000073942:T-Cell Acute Lymphocytic Leukemia Protein 1; D016896:Treatment Outcome
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D004268:DNA-Binding Proteins; D006657:Histones; D018398:Homeodomain Proteins; D009687:Nuclear Proteins; D063146:Polycomb-Group Proteins; D011518:Proto-Oncogene Proteins; D000073942:T-Cell Acute Lymphocytic Leukemia Protein 1; C499311:RAG2 protein, human; C064658:RAG-1 protein; C067143:TAL1 protein, human