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Genome-wide signatures of differential DNA methylation in pediatric acute lymphoblastic leukemia

Jessica Nordlund1, Christofer L Bäcklin2, Per Wahlberg1, Stephan Busche3, Eva C Berglund1, Maija-Leena Eloranta4, Trond Flaegstad145, Erik Forestier146, Britt-Marie Frost147, Arja Harila-Saari1489, Mats Heyman149, Ólafur G Jónsson1014, Rolf Larsson2, Josefine Palle1147, Lars Rönnblom4, Kjeld Schmiegelow1114, Daniel Sinnett12, Stefan Söderhäll147, Tomi Pastinen133, Mats G Gustafsson2, Gudmar Lönnerholm147 and Ann-Christine Syvänen1*

Author Affiliations

1 Department of Medical Sciences, Molecular Medicine and Science for Life Laboratory, Uppsala University, Uppsala 75185, Sweden

2 Department of Medical Sciences, Cancer Pharmacology and Computational Medicine, Uppsala University, Uppsala 75185, Sweden

3 Department of Human Genetics, McGill University, Montréal, Québec H3A0G1, Canada

4 Department of Medical Sciences, Rheumatology, Uppsala University, Uppsala 75185, Sweden

5 Department of Pediatrics, Tromsø University and University Hospital, Tromsø N-9038, Norway

6 Department of Medical Biosciences, University of Umeå, Umeå 90185, Sweden

7 Department of Women’s and Children’s Health, Pediatric Oncology, Uppsala University, Uppsala 75185, Sweden

8 Department of Pediatrics and Adolescence, Oulu University Hospital, Oulu 90029, Finland

9 Childhood Cancer Research Unit, Karolinska Institutet, Astrid Lindgren Children’s Hospital, Karolinska University Hospital, Stockholm 17176, Sweden

10 Pediatric Hematology-Oncology, Children’s Hospital, Barnaspitali Hringsins, Landspitali University Hospital, Reykjavik 101, Iceland

11 ediatrics and Adolescent Medicine, Rigshospitalet, and the Medical Faculty, Institute of Clinical Medicine, University of Copenhagen, Copenhagen 2100, Denmark

12 Division of Hematology-Oncology, CHU Sainte-Justine Research Center, Department of Pediatrics, University of Montreal, Montréal, Québec, Canada

13 Department of Human Genetics, McGill University and Genome Quebec Innovation Center, Montréal, Québec H3T1C5, Canada

14 For the Nordic Society of Pediatric Hematology and Oncology (NOPHO

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Genome Biology 2013, 14:r105  doi:10.1186/gb-2013-14-9-r105

Published: 24 September 2013

Abstract

Background

Although aberrant DNA methylation has been observed previously in acute lymphoblastic leukemia (ALL), the patterns of differential methylation have not been comprehensively determined in all subtypes of ALL on a genome-wide scale. The relationship between DNA methylation, cytogenetic background, drug resistance and relapse in ALL is poorly understood.

Results

We surveyed the DNA methylation levels of 435,941 CpG sites in samples from 764 children at diagnosis of ALL and from 27 children at relapse. This survey uncovered four characteristic methylation signatures. First, compared with control blood cells, the methylomes of ALL cells shared 9,406 predominantly hypermethylated CpG sites, independent of cytogenetic background. Second, each cytogenetic subtype of ALL displayed a unique set of hyper- and hypomethylated CpG sites. The CpG sites that constituted these two signatures differed in their functional genomic enrichment to regions with marks of active or repressed chromatin. Third, we identified subtype-specific differential methylation in promoter and enhancer regions that were strongly correlated with gene expression. Fourth, a set of 6,612 CpG sites was predominantly hypermethylated in ALL cells at relapse, compared with matched samples at diagnosis. Analysis of relapse-free survival identified CpG sites with subtype-specific differential methylation that divided the patients into different risk groups, depending on their methylation status.

Conclusions

Our results suggest an important biological role for DNA methylation in the differences between ALL subtypes and in their clinical outcome after treatment.