Transcription-coupled genetic instability marks acute lymphoblastic leukemia structural variation hotspots
Open Access
- 19 July 2016
- journal article
- research article
- Published by eLife Sciences Publications, Ltd in eLife
Abstract
Progression of malignancy to overt disease requires multiple genetic hits. Activation-induced deaminase (AID) can drive lymphomagenesis by generating off-target DNA breaks at loci that harbor highly active enhancers and display convergent transcription. The first active transcriptional profiles from acute lymphoblastic leukemia (ALL) patients acquired here reveal striking similarity at structural variation (SV) sites. Specific transcriptional features, namely convergent transcription and Pol2 stalling, were detected at breakpoints. The overlap was most prominent at SV with recognition motifs for the recombination activating genes (RAG). We present signal feature analysis to detect vulnerable regions and quantified from human cells how convergent transcription contributes to R-loop generation and RNA polymerase stalling. Wide stalling regions were characterized by high DNAse hypersensitivity and unusually broad H3K4me3 signal. Based on 1382 pre-B-ALL patients, the ETV6-RUNX1 fusion positive patients had over ten-fold elevation in RAG1 while high expression of AID marked pre-B-ALL lacking common cytogenetic changes.Keywords
Funding Information
- Suomen Kulttuurirahasto (00150214)
- Itä-Suomen Yliopisto
- The Finnish Cancer Foundation
- Emil Aaltosen Säätiö
- Suomen Akatemia (276634)
- Tampereen Yliopisto
- Sigrid Juselius Foundation
- Suomen Akatemia (277816)
- Jane ja Aatos Erkon Säätiö
- Paulo Foundation
- Lastentautien Tutkimussäätiö
- Competitive State Research Financing of the Expert Responsibility area of Tampere University Hospital
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