Whole genome bisulfite sequencing of acute lymphoblastic leukemia cells. P. Wahlberg1, A. Lundmark1, J. Nordlund1, A. Raine1, S. Busche5, E. Forestier2,4, T. Pastinen5,6, G. Lönnerholm3,4, A.-C. Syvänen1 1) Department of Medical Sciences, Molecular Medicine and Science for Life Laboratory, Uppsala University, Sweden; 2) Department of Medical Biosciences, University of Umeå, Sweden; 3) Department of Childrens and Womens Health, Uppsala University, Sweden; 4) For the Nordic Society of Pediatric Hematology and Oncology (NOPHO); 5) Department of Human Genetics, McGill University, Montréal, Québec H3A0G1, Canada; 6) Department of Human Genetics, McGill University and Genome Quebec Innovation Center, Montréal, Québec H3T1C5, Canada.
Acute lymphoblastic leukemia (ALL) is the most common pediatric cancer in the developed countries. Aberrant patterns of methylation have been associated with cancer and epigenetic modifiers such as the ten eleven translocation (TET) family of enzymes and DNA methyltransferases (DNMTs) are recurrently mutated in leukemic cancers. We have previously documented large differences between ALL subtypes and normal B- and T-cells using the Illumina Human 450K BeadArray platform. To further investigate the distribution of CpG methylation in ALL cells, we generated Whole Genome Bisulfite Sequencing (WGBS) data at high coverage (20-30X) of four Swedish pediatric ALL patients with different genetic subtypes of ALL. In our study we also included low-pass (~5X) WGBS data from B- (n=8) and T-cells (n=14) and additional BCP-ALL t(12;21) patients (n=3). Comparison of the WGBS data from the ALL methylomes revealed that the ALL methylome generally have higher methylation levels than B- and T-cells. Specifically we observed aberrant CpG island methylation in ALL samples with the t(12;21)ETV-RUNX1 translocation. Principal component analysis (PCA) of methylation data from CpG islands showed limited variation between samples, with the exception of the ALL subtype t(12;21)ETV-RUNX1 that formed a separate cluster. On the contrary, PCA using methylation levels from CpG island shores reveal distinct cell-type specific T- and B-cell clusters separated from the ALL samples. The DMR analysis between ALL samples and B- and T-cell identified between 9,235 - 15,924 DMRs with an average size of 1 kb and in sizes from 200 bp up to 43 kb. In the ALL subtype t(12;21)ETV-RUNX1 we identified large-scale locus specific DMRs at cancer-related genes that were associated with increased RNA expression. ALL specific DMRs and cell-type specific B- and T-cell DMRs are distributed across the genome in a similar manner with the exception of hypermethylated DMRs annotated to CpG islands that are enriched in ALL samples. DMRs are under-represented in intergenic regions and enriched to regions associated to genes. The fact that the DMRs overlap with and are enriched to functional sequences indicates that they have a functional role in ALL.
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