Site- and allele-specific polycomb dysregulation in T-cell leukaemia.
Navarro JM, Touzart A, Pradel LC, Loosveld M, Koubi M, Fenouil R, Le Noir S, Maqbool MA, Morgado E, Gregoire C, Jaeger S, Mamessier E, Pignon C, Hacein-Bey-Abina S, Malissen B, Gut M, Gut IG, Dombret H, Macintyre EA, Howe SJ, Gaspar HB, Thrasher AJ, Ifrah N, Payet-Bornet D, Duprez E, Andrau JC, Asnafi V, Nadel B
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.Lire l‘article