Site- and allele-specific polycomb dysregulation in T-cell leukaemia
- PMID: 25615415
- PMCID: PMC4317503
- DOI: 10.1038/ncomms7094
Site- and allele-specific polycomb dysregulation in T-cell leukaemia
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.
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References
-
- Teitell M. A. & Pandolfi P. P. Molecular genetics of acute lymphoblastic leukemia. Annu. Rev. Pathol. 4, 175–198 (2009). - PubMed
-
- Van Vlierberghe P., Pieters R., Beverloo H. B. & Meijerink J. P. Molecular-genetic insights in paediatric T-cell acute lymphoblastic leukaemia. Br. J. Haematol. 143, 153–168 (2008). - PubMed
-
- Mouthon M. A. et al. Expression of tal-1 and GATA-binding proteins during human hematopoiesis. Blood 81, 647–655 (1993). - PubMed
-
- Herblot S., Steff A. M., Hugo P., Aplan P. D. & Hoang T. SCL and LMO1 alter thymocyte differentiation: inhibition of E2A-HEB function and pre-T alpha chain expression. Nat. Immunol. 1, 138–144 (2000). - PubMed
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