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Nat Commun. 2015 Jan 23;6:6094. doi: 10.1038/ncomms7094.

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

Author information

1
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.
2
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.
3
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.
4
CRCM Inserm U1068, Institut Paoli Calmettes; Aix-Marseille Université, UM 105; CNRS UMR7258, 13009 Marseille, France.
5
Biotherapy Department, INSERM U429, Hôpital Necker-Enfants-Malades, 149 rue de Sèvres, 75015 Paris, France.
6
Centro Nacional de Análisis Genómico, 08028 Barcelona, Spain.
7
Department of Hematology, AP-HP Hôpital St-Louis, 75010 Paris, France.
8
Centre for Immunodeficiency, Molecular and Cellular Immunology, Institute of Child Health, University College London, London WC1N 1EH, UK.
9
Services des Maladies du sang CHU and UMR Inserm U 892/CNRS 6299, 49933 Angers, France.
10
Laboratoire Hématologie, APHM, 13385 Marseille, France.

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.

PMID:
25615415
PMCID:
PMC4317503
DOI:
10.1038/ncomms7094
[Indexed for MEDLINE]
Free PMC Article

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