Transcription-coupled Genetic Instability Marks Acute Lymphoblastic Leukemia Structural Variation Hotspots

Overview

Journal Elife

Specialty Biology

Date 2016 Jul 20

PMID 27431763

Citations 26

Authors

Merja Heinaniemi

Tapio Vuorenmaa

Susanna Teppo

Minna U Kaikkonen

Maria Bouvy-Liivrand

Juha Mehtonen

Henri Niskanen

Vasilios Zachariadis

Saara Laukkanen

Thomas Liuksiala

Kaisa Teittinen

Olli Lohi

Affiliations

Soon will be listed here.

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.

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References

Schatz D, Swanson P . V(D)J recombination: mechanisms of initiation. Annu Rev Genet. 2011; 45:167-202. DOI: 10.1146/annurev-genet-110410-132552. View

Wang X, Fan M, Kalis S, Wei L, Scharff M . A source of the single-stranded DNA substrate for activation-induced deaminase during somatic hypermutation. Nat Commun. 2014; 5:4137. PMC: 4154566. DOI: 10.1038/ncomms5137. View

Hnisz D, Abraham B, Lee T, Lau A, Saint-Andre V, Sigova A . Super-enhancers in the control of cell identity and disease. Cell. 2013; 155(4):934-47. PMC: 3841062. DOI: 10.1016/j.cell.2013.09.053. View

Qian J, Wang Q, Dose M, Pruett N, Kieffer-Kwon K, Resch W . B cell super-enhancers and regulatory clusters recruit AID tumorigenic activity. Cell. 2014; 159(7):1524-37. PMC: 4272762. DOI: 10.1016/j.cell.2014.11.013. View

Rao S, Huntley M, Durand N, Stamenova E, Bochkov I, Robinson J . A 3D map of the human genome at kilobase resolution reveals principles of chromatin looping. Cell. 2014; 159(7):1665-80. PMC: 5635824. DOI: 10.1016/j.cell.2014.11.021. View

Maia A, van der Velden V, Harrison C, Szczepanski T, Williams M, Griffiths M . Prenatal origin of hyperdiploid acute lymphoblastic leukemia in identical twins. Leukemia. 2003; 17(11):2202-6. DOI: 10.1038/sj.leu.2403101. View

Meng F, Du Z, Federation A, Hu J, Wang Q, Kieffer-Kwon K . Convergent transcription at intragenic super-enhancers targets AID-initiated genomic instability. Cell. 2014; 159(7):1538-48. PMC: 4322776. DOI: 10.1016/j.cell.2014.11.014. View

Kaikkonen M, Spann N, Heinz S, Romanoski C, Allison K, Stender J . Remodeling of the enhancer landscape during macrophage activation is coupled to enhancer transcription. Mol Cell. 2013; 51(3):310-25. PMC: 3779836. DOI: 10.1016/j.molcel.2013.07.010. View

Papaemmanuil E, Rapado I, Li Y, Potter N, Wedge D, Tubio J . RAG-mediated recombination is the predominant driver of oncogenic rearrangement in ETV6-RUNX1 acute lymphoblastic leukemia. Nat Genet. 2014; 46(2):116-25. PMC: 3960636. DOI: 10.1038/ng.2874. View

10.

Core L, Martins A, Danko C, Waters C, Siepel A, Lis J . Analysis of nascent RNA identifies a unified architecture of initiation regions at mammalian promoters and enhancers. Nat Genet. 2014; 46(12):1311-20. PMC: 4254663. DOI: 10.1038/ng.3142. View

11.

Huang F, Yu K, Balter B, Selsing E, Oruc Z, Khamlichi A . Sequence dependence of chromosomal R-loops at the immunoglobulin heavy-chain Smu class switch region. Mol Cell Biol. 2007; 27(16):5921-32. PMC: 1952116. DOI: 10.1128/MCB.00702-07. View

12.

Skourti-Stathaki K, Kamieniarz-Gdula K, Proudfoot N . R-loops induce repressive chromatin marks over mammalian gene terminators. Nature. 2014; 516(7531):436-9. PMC: 4272244. DOI: 10.1038/nature13787. View

13.

Sulong S, Moorman A, Irving J, Strefford J, Konn Z, Case M . A comprehensive analysis of the CDKN2A gene in childhood acute lymphoblastic leukemia reveals genomic deletion, copy number neutral loss of heterozygosity, and association with specific cytogenetic subgroups. Blood. 2008; 113(1):100-7. DOI: 10.1182/blood-2008-07-166801. View

14.

Swaminathan S, Klemm L, Park E, Papaemmanuil E, Ford A, Kweon S . Mechanisms of clonal evolution in childhood acute lymphoblastic leukemia. Nat Immunol. 2015; 16(7):766-774. PMC: 4475638. DOI: 10.1038/ni.3160. View

15.

Ginno P, Lim Y, Lott P, Korf I, Chedin F . GC skew at the 5' and 3' ends of human genes links R-loop formation to epigenetic regulation and transcription termination. Genome Res. 2013; 23(10):1590-600. PMC: 3787257. DOI: 10.1101/gr.158436.113. View

16.

Scheidegger A, Nechaev S . RNA polymerase II pausing as a context-dependent reader of the genome. Biochem Cell Biol. 2015; 94(1):82-92. PMC: 4728023. DOI: 10.1139/bcb-2015-0045. View

17.

Roberts K, Mullighan C . Genomics in acute lymphoblastic leukaemia: insights and treatment implications. Nat Rev Clin Oncol. 2015; 12(6):344-57. DOI: 10.1038/nrclinonc.2015.38. View

18.

Alt F, Zhang Y, Meng F, Guo C, Schwer B . Mechanisms of programmed DNA lesions and genomic instability in the immune system. Cell. 2013; 152(3):417-29. PMC: 4382911. DOI: 10.1016/j.cell.2013.01.007. View

19.

Pefanis E, Wang J, Rothschild G, Lim J, Chao J, Rabadan R . Noncoding RNA transcription targets AID to divergently transcribed loci in B cells. Nature. 2014; 514(7522):389-93. PMC: 4372240. DOI: 10.1038/nature13580. View

20.

Paulsson K, Lilljebjorn H, Biloglav A, Olsson L, Rissler M, Castor A . The genomic landscape of high hyperdiploid childhood acute lymphoblastic leukemia. Nat Genet. 2015; 47(6):672-6. DOI: 10.1038/ng.3301. View