Epigenetic remodeling in B-cell acute lymphoblastic leukemia occurs in two tracks and employs embryonic stem cell-like signatures

This is the publisher’s final pdf. The published article is copyrighted by the author(s) and published by Oxford University Press on behalf of Nucleic Acids Research. The published article can be found at: http://nar.oxfordjournals.org/.We investigated DNA methylomes of pediatric B-cell\ud acute lymphoblastic leukemias (B-ALLs) using\ud whole-genome bisulfite sequencing and high-definition\ud microarrays, along with RNA expression\ud profiles. Epigenetic alteration of B-ALLs occurred in\ud two tracks: de novo methylation of small functional\ud compartments and demethylation of large intercompartmental\ud backbones. The deviations were exaggerated\ud in lamina-associated domains, with differences\ud corresponding to methylation clusters and/or\ud cytogenetic groups. Our data also suggested a pivotal\ud role of polycomb and CTBP2 in de novo methylation,\ud which may be traced back to bivalency status\ud of embryonic stem cells. Driven by these potent epigenetic\ud modulations, suppression of polycomb target\ud genes was observed along with disruption of developmental\ud fate and cell cycle and mismatch repair\ud pathways and altered activities of key upstream regulators