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11CNAG - Centro Nacional de Análisi Genómico (Generalitat de Catalunya - Departament de SalutGeneralitat de Catalunya - Departament d'InnovacióMinisterio de Ciendia e InnovaciónParc Científic de Barcelona baldiri reixac, 4 pcb - tower i 08028 Barcelona - Spain)
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.
https://hal-amu.archives-ouvertes.fr/hal-01612097 Contributor : Lionel SpinelliConnect in order to contact the contributor Submitted on : Monday, January 6, 2020 - 5:40:59 PM Last modification on : Tuesday, July 5, 2022 - 10:20:53 AM Long-term archiving on: : Tuesday, April 7, 2020 - 11:47:02 PM