title: Transcription-coupled genetic instability marks acute lymphoblastic leukemia structural variation hotspots.
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.
authors.affiliation: School of Medicine, University of Eastern Finland, Kuopio, Finland.
authors.forename: Merja
authors.identifier: 0000-0001-6190-3439
authors.initials: M
authors.lastname: Heinäniemi
authors.affiliation: School of Medicine, University of Eastern Finland, Kuopio, Finland.|A. I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland.
authors.forename: Tapio
authors.initials: T
authors.lastname: Vuorenmaa
authors.affiliation: School of Medicine, University of Tampere, Tampere, Finland.
authors.forename: Susanna
authors.identifier: 0000-0003-2569-8030
authors.initials: S
authors.lastname: Teppo
authors.affiliation: A. I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland.
authors.forename: Minna U
authors.initials: MU
authors.lastname: Kaikkonen
authors.affiliation: School of Medicine, University of Eastern Finland, Kuopio, Finland.
authors.forename: Maria
authors.initials: M
authors.lastname: Bouvy-Liivrand
authors.affiliation: School of Medicine, University of Eastern Finland, Kuopio, Finland.
authors.forename: Juha
authors.initials: J
authors.lastname: Mehtonen
authors.affiliation: A. I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland.
authors.forename: Henri
authors.initials: H
authors.lastname: Niskanen
authors.affiliation: Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Vasilios
authors.initials: V
authors.lastname: Zachariadis
authors.affiliation: School of Medicine, University of Tampere, Tampere, Finland.
authors.forename: Saara
authors.initials: S
authors.lastname: Laukkanen
authors.affiliation: School of Medicine, University of Tampere, Tampere, Finland.
authors.forename: Thomas
authors.initials: T
authors.lastname: Liuksiala
authors.affiliation: School of Medicine, University of Tampere, Tampere, Finland.
authors.forename: Kaisa
authors.initials: K
authors.lastname: Teittinen
authors.affiliation: School of Medicine, University of Tampere, Tampere, Finland.|Tampere University Hospital, Tampere, Finland.
authors.forename: Olli
authors.identifier: 0000-0001-9195-0797
authors.initials: O
authors.lastname: Lohi
mesh_terms: D003564:Cytidine Deaminase / Q000378:metabolism; D042822:Genomic Instability; D006801:Humans; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000473:pathology*; D012319:RNA Polymerase II / Q000378:metabolism; D014158:Transcription, Genetic; D000098830:AICDA (Activation-Induced Cytidine Deaminase)
chemical_list: D012319:RNA Polymerase II; D000098830:AICDA (Activation-Induced Cytidine Deaminase); D003564:Cytidine Deaminase
keywords: GRO-seq; chromosomes; genes; genetic instability; human; human biology; leukemia; medicine; signal feature analysis; transcription