Journal Article

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

Gut, Ivo G., Nadel, Bertrand, Loosveld, Marie, Touzart, Aurore, Howe, Steven J., Koubi, Myriam, Malissen, Bernard, Dombret, Hervé, Fenouil, Romain, Pignon, Charles, Andrau, Jean-Christophe, Gut, Marta, Jaeger, Sebastien, Le Noir, Sandrine, Maqbool, Muhammad Ahmad, Gaspar, H. Bobby, Morgado, Ester, Hacein-Bey-Abina, Salima, Gregoire, Claude, Macintyre, Elizabeth A., Thrasher, Adrian J., Payet-Bornet, Dominique, Navarro, Jean-Marc, Mamessier, Emilie, Asnafi, Vahid, Duprez, Estelle, Pradel, Lydie C., Ifrah, Norbert

2015

Overview

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. TAL1 is frequently deregulated in T-cell acute lymphoblastic leukaemias, but the mechanism remains largely unclear. Here the authors show that microinsertions upstream of TAL1 cause its epigenetic reactivation, and that the mode of TAL1 activation correlates with prognosis.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Pub. Group
• Subject: 13/106 / 42/44 / 42/89 / 631/67/1990/291/1621/1916 / 631/67/68/2486 / 692/308 / Acetylation / Adult / Alleles / Base Sequence / Basic Helix-Loop-Helix Transcription Factors - metabolism / Cancer / Chromatin Immunoprecipitation / Deregulation / DNA-Binding Proteins - metabolism / Epigenesis, Genetic / Gene Expression Regulation, Leukemic / Genetic Loci / Heterogeneity / Histones - metabolism / Homeodomain Proteins - metabolism / Humanities and Social Sciences / Humans / Immunology / Immunotherapy / Jurkat Cells / Leukemia / Life Sciences / Methylation / Molecular Sequence Data / multidisciplinary / Mutagenesis, Insertional / Nuclear Proteins - metabolism / Plasmids - genetics / Polycomb-Group Proteins - genetics / Polycomb-Group Proteins - metabolism / Precursor T-Cell Lymphoblastic Leukemia-Lymphoma - genetics / Proto-Oncogene Proteins - metabolism / Science / Science (multidisciplinary) / Survival Analysis / T-Cell Acute Lymphocytic Leukemia Protein 1 / Treatment Outcome