title: Epigenetic remodeling in B-cell acute lymphoblastic leukemia occurs in two tracks and employs embryonic stem cell-like signatures.
abstract: 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.
authors.affiliation: Department of Epidemiology and Biostatistics, University of California at San Francisco, San Francisco, CA 94158, USA Department of Laboratory Medicine, Yonsei University College of Medicine, Seoul 120752, Republic of Korea.
authors.forename: Seung-Tae
authors.initials: ST
authors.lastname: Lee
authors.affiliation: Blood Systems Research Institute, University of California at San Francisco, San Francisco, CA 94158, USA Liver Center and Department of Laboratory Medicine, University of California at San Francisco, San Francisco, CA 94158, USA.
authors.forename: Marcus O
authors.initials: MO
authors.lastname: Muench
authors.affiliation: Blood Systems Research Institute, University of California at San Francisco, San Francisco, CA 94158, USA.
authors.forename: Marina E
authors.initials: ME
authors.lastname: Fomin
authors.affiliation: Department of Epidemiology and Biostatistics, University of California at San Francisco, San Francisco, CA 94158, USA.
authors.forename: Jianqiao
authors.initials: J
authors.lastname: Xiao
authors.affiliation: Department of Epidemiology and Biostatistics, University of California at San Francisco, San Francisco, CA 94158, USA.
authors.forename: Mi
authors.initials: M
authors.lastname: Zhou
authors.affiliation: Department of Epidemiology and Biostatistics, University of California at San Francisco, San Francisco, CA 94158, USA.
authors.forename: Adam
authors.initials: A
authors.lastname: de Smith
authors.affiliation: Unidad de Hematopatología, Servicio de Anatomía Patológica, Hospital Clínic, Universitat de Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona 08036, Spain.
authors.forename: José I
authors.initials: JI
authors.lastname: Martín-Subero
authors.affiliation: Centro Nacional de Análisis Genómico, Parc Científic de Barcelona, Barcelona 08036, Spain.
authors.forename: Simon
authors.initials: S
authors.lastname: Heath
authors.affiliation: Department of Public Health, Oregon State University, Corvallis, OR, 97331 USA.
authors.forename: E Andres
authors.initials: EA
authors.lastname: Houseman
authors.affiliation: Cancer Research Institute, University of California at San Francisco, San Francisco, CA 94158, USA.
authors.forename: Ritu
authors.initials: R
authors.lastname: Roy
authors.affiliation: Department of Neurological Surgery, University of California at San Francisco, San Francisco, CA 94158, USA.
authors.forename: Margaret
authors.initials: M
authors.lastname: Wrensch
authors.affiliation: Department of Neurological Surgery, University of California at San Francisco, San Francisco, CA 94158, USA.
authors.forename: John
authors.initials: J
authors.lastname: Wiencke
authors.affiliation: Division of Epidemiology, School of Public Health, University of California at Berkeley, Berkeley, CA 94720, USA.
authors.forename: Catherine
authors.initials: C
authors.lastname: Metayer
authors.affiliation: Department of Epidemiology and Biostatistics, University of California at San Francisco, San Francisco, CA 94158, USA Department of Neurological Surgery, University of California at San Francisco, San Francisco, CA 94158, USA joe.wiemels@ucsf.edu.
authors.forename: Joseph L
authors.initials: JL
authors.lastname: Wiemels
mesh_terms: D000429:Alcohol Oxidoreductases / Q000235:genetics; D001402:B-Lymphocytes / Q000378:metabolism* / Q000473:pathology; D002648:Child; D056970:Co-Repressor Proteins; D018899:CpG Islands / Q000235:genetics; D019175:DNA Methylation; D053595:Embryonic Stem Cells / Q000378:metabolism*; D057890:Epigenomics / Q000379:methods*; D020869:Gene Expression Profiling / Q000379:methods*; D006657:Histones / Q000378:metabolism; D006801:Humans; D008239:Lysine / Q000378:metabolism; D008745:Methylation; D009363:Neoplasm Proteins; D009419:Nerve Tissue Proteins / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis; D063151:Polycomb Repressive Complex 2 / Q000235:genetics; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics*; D054448:Precursor Cells, B-Lymphoid / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction / Q000235:genetics; D014157:Transcription Factors
chemical_list: D056970:Co-Repressor Proteins; D006657:Histones; D009363:Neoplasm Proteins; D009419:Nerve Tissue Proteins; C430461:SUZ12 protein, human; D014157:Transcription Factors; D000429:Alcohol Oxidoreductases; C421248:CTBP2 protein, human; D063151:Polycomb Repressive Complex 2; D008239:Lysine