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

Jean-Marc Navarro 1 Aurore Touzart 2 Lydie Pradel 1 Marie Loosveld 1 Myriam Koubi 3 Romain Fenouil 1 Sandrine Le Noir 2 Muhammad Ahmad Maqbool 1 Ester Morgado 1 Claude Gregoire 1 Sebastien Jaeger 1 Emilie Mamessier 1 Charles Pignon 1 Salima Hacein-Bey-Abina 2 Bernard Malissen 1 Marta Gut 4 Ivo G. Gut 4 Hervé Dombret 5 Elizabeth A. Macintyre 2 Steven J. Howe 6 H. Bobby Gaspar 6 Adrian J. Thrasher 6 Norbert Ifrah 7 Dominique Payet-Bornet 1 Estelle Duprez 8 Jean-Christophe Andrau 1 Vahid Asnafi 2 Bertrand Nadel 1
1 CIML - Centre d'Immunologie de Marseille - Luminy
2 INEM - UM 111 (UMR 8253 / U1151) - Institut Necker Enfants-Malades
3 CRCM - Centre de Recherche en Cancérologie de Marseille
4 CNAG - Centro Nacional de Analisis Genomico [Barcelona]
5 AP-HP - Hopital Saint-Louis [AP-HP]
6 UCL - University College of London [London]
7 CRCNA - Centre de Recherche en Cancérologie Nantes-Angers
8 APHM - Assistance Publique - Hôpitaux de Marseille
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.
Keywords : Cancer epigenetics Medical research T-cell lymphoma
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UNIV-AMU | CNRS | UNIV-PARIS5 | CRCM | USPC | UNIV-PARIS | UP-SANTE | UNAM | CERCLE | CRCNA

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Jean-Marc Navarro, Aurore Touzart, Lydie Pradel, Marie Loosveld, Myriam Koubi, et al.. Site- and allele-specific polycomb dysregulation in T-cell leukaemia. Nature Communications, Nature Publishing Group, 2015, 6 (1), pp.6094. ⟨10.1038/ncomms7094⟩. ⟨hal-01612097⟩

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