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

• DOI: 10.1038/ncomms7094
• Publication Date: 2015-01-23T13:40:25Z
• Authors: Jean-Marc Navarro; Aurore Touzart; Lydie C. Pradel; Marie Loosveld; Myriam Koubi; Romain Fenouil; Sandrine Le Noir; Muhammad Ahmad Ma...; Ester Morgado; Claude Gregoire; Sebastien Jaeger; Emilie Mamessier; Charles Pignon; Salima Hacein-Bey...; Bernard Malissen; Marta Gut; Ivo G. Gut; Hervé Dombret; Elizabeth A. Maci...; Steven J. Howe; H. Bobby Gaspar; Adrian J. Thrasher; Norbert Ifrah; Dominique Payet-B...; Estelle Duprez; Jean-Christophe A...; Vahid Asnafi; Bertrand Nadel
• Keywords: Adult; 0301 basic medicine; Chromatin Immunoprecipitation; [SDV]Life Sciences [q-bio]; Molecular Sequence Data; 610; Polycomb-Group Proteins; [SDV.CAN]Life Sciences [q-bio]/Cancer; Methylation; Article; Epigenesis, Genetic; Histones; Jurkat Cells; 03 medical and health sciences; Medical research; Cancer epigenetics; [SDV.CAN] Life Sciences [q-bio]/Cancer; Basic Helix-Loop-Helix Transcription Factors; Humans; Alleles; Homeodomain Proteins; Base Sequence; Gene Expression Regulation, Leukemic; Nuclear Proteins; Acetylation; [SDV.IMM.IMM]Life Sciences [q-bio]/Immunology/Immunotherapy; [SDV] Life Sciences [q-bio]; DNA-Binding Proteins; Mutagenesis, Insertional; Genetic Loci; T-cell lymphoma; [SDV.IMM.IMM] Life Sciences [q-bio]/Immunology/Immunotherapy; Plasmids

AbstractT-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.