Epigenetic remodeling in B-cell acute lymphoblastic leukemia occurs in two tracks and employs embryonic stem cell-like signatures
Authors
Seung-Tae Lee ; Marcus O. Muench ; Marina E. Fomin ; Jianqiao Xiao ; Mi Zhou ; Adam de Smith ; Jos´e I. Mart´ın-Subero ; Simon Heath ; E. Andres Houseman ; Ritu Roy ; Margaret Wrensch ; John Wiencke ; Catherine Metayer ; Joseph L. Wiemels
We investigated DNA methylomes of pediatric B-cell acute lymphoblastic leukemias (B-ALLs) using whole-genome bisulfite sequencing and high-definition microarrays, along with RNA expression profiles. Epigenetic alteration of B-ALLs occurred in two tracks: de novo methylation of small functional compartments and demethylation of large inter-compartmental backbones. The deviations were exaggerated in lamina-associated domains, with differences corresponding to methylation clusters and/or cytogenetic groups. Our data also suggested a pivotal role of polycomb and CTBP2 in de novo methylation, which may be traced back to bivalency status of embryonic stem cells. Driven by these potent epigenetic modulations, suppression of polycomb target genes was observed along with disruption of developmental fate and cell cycle and mismatch repair pathways and altered activities of key upstream regulators.