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Title: Site- and allele-specific de-silencing of polycomb repressive activity by insertional oncogenesis: a new recurrent mechanism of TAL1 activation in T-ALL      
dateReleased:
07-10-2014
description:
T-cell acute lymphoblastic leukemia’s (T-ALL) are malignant proliferations of thymocytes occurring through a large diversity of genomic and epigenetic alteration. TAL1 is amongst the most frequently deregulated oncogenes. Known TAL1 dysregulation mechanisms consist of t(1;14) translocations and SIL-TAL deletions. Yet, over half of TAL1+ cases lack TAL1 lesions, pointing to unrecognized (epi)genetic deregulation mechanisms. In such “unresolved cases”, TAL1 expression can be mono-allelic, compatible with a direct alteration in cis within or around the TAL1 gene, or bi-allelic, likely reflecting indirect deregulation in trans. Using ChIP-seq, 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 revealed that >20% of mono-allelic TAL1+ patients without previously known alterations display micro-insertions 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 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 reveal a new adverse mechanism of mono-allelic oncogenic activation through site-specific epigenetic de-silencing. ChIP-seq experiments were designed to asses the dynamic enrichment of H3K27me3 and H3K27ac marks on the genome and understand the mechanisms underlying the TAL1 expression cys-regulation.
privacy:
not applicable
aggregation:
instance of dataset
ID:
E-GEOD-59257
refinement:
raw
alternateIdentifiers:
59257
keywords:
functional genomics
dateModified:
08-14-2014
availability:
available
types:
gene expression
name:
Homo sapiens
accessURL: https://www.ebi.ac.uk/arrayexpress/files/E-GEOD-59257/E-GEOD-59257.raw.1.zip
storedIn:
ArrayExpress
qualifier:
gzip compressed
format:
TXT
accessType:
download
authentication:
none
authorization:
none
accessURL: https://www.ebi.ac.uk/arrayexpress/files/E-GEOD-59257/E-GEOD-59257.processed.1.zip
storedIn:
ArrayExpress
qualifier:
gzip compressed
format:
TXT
accessType:
download
authentication:
none
authorization:
none
accessURL: https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE59257
storedIn:
Gene Expression Omnibus
qualifier:
not compressed
format:
HTML
accessType:
landing page
primary:
true
authentication:
none
authorization:
none
abbreviation:
EBI
homePage: http://www.ebi.ac.uk/
ID:
SCR:004727
name:
European Bioinformatics Institute
homePage: https://www.ebi.ac.uk/arrayexpress/
ID:
SCR:002964
name:
ArrayExpress
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