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Elife. 2016 Jul 19;5. pii: e13087. doi: 10.7554/eLife.13087.

Transcription-coupled genetic instability marks acute lymphoblastic leukemia structural variation hotspots.

Author information

1
School of Medicine, University of Eastern Finland, Kuopio, Finland.
2
A. I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland.
3
School of Medicine, University of Tampere, Tampere, Finland.
4
Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
5
Tampere University Hospital, Tampere, Finland.

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:

GRO-seq; chromosomes; genes; genetic instability; human; human biology; leukemia; medicine; signal feature analysis; transcription

PMID:
27431763
PMCID:
PMC4951197
DOI:
10.7554/eLife.13087
[Indexed for MEDLINE]
Free PMC Article

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