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.
Highlights
In precursor lymphoblastic leukemia, primary genetic lesions often arise in utero (Wiemels et al, 1999; Mori et al, 2002; Maia et al, 2003, Bateman et al, 2015), while the onset of overt disease requires additional genetic alterations
The maturing lymphoid cells are vulnerable to off-target effects downstream of recombination activating genes (RAG) and Activationinduced deaminase (AID) activity that is required for immune gene rearrangement (Meng et al, 2014; Qian et al, 2014, Papaemmanuil et al, 2014, Swaminathan et al, 2015)
Wilcoxon rank sum test p-value is indicated for differential RAG1 expression in the ETV6-RUNX1 subtype (N = 153, patients with cytogenetic subtype information N = 1008). (D–F) Alternative representation of discrete expression states for RAG1, RAG2, and AICDA, respectively
Summary
Primary genetic lesions often arise in utero (Wiemels et al, 1999; Mori et al, 2002; Maia et al, 2003, Bateman et al, 2015), while the onset of overt disease requires additional genetic alterations. Whole-genome sequencing (WGS) of ETV6-RUNX1 ( known as TEL-AML1) positive acute leukemias suggested that the secondary lesions are predominantly caused by off-target activity of the RAG complex (Papaemmanuil et al, 2014). WGS in leukemia have been reported from several pre-B-ALL subtypes (Andersson et al, 2015; Holmfeld et al, 2013; Paulsson et al, 2015; Zhang et al, 2012), resulting in a comprehensive characterization of the underlying genetic alterations. The research focus on leukemia genetics is moving into characterization of the mechanisms by which these lesions occur and the consequences of the resulting clonal heterogeneity.
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