title: New insights into the biology and origin of mature aggressive B-cell lymphomas by combined epigenomic, genomic, and transcriptional profiling.
abstract: Lymphomas are assumed to originate at different stages of lymphocyte development through chromosomal aberrations. Thus, different lymphomas resemble lymphocytes at distinct differentiation stages and show characteristic morphologic, genetic, and transcriptional features. Here, we have performed a microarray-based DNA methylation profiling of 83 mature aggressive B-cell non-Hodgkin lymphomas (maB-NHLs) characterized for their morphologic, genetic, and transcriptional features, including molecular Burkitt lymphomas and diffuse large B-cell lymphomas. Hierarchic clustering indicated that methylation patterns in maB-NHLs were not strictly associated with morphologic, genetic, or transcriptional features. By supervised analyses, we identified 56 genes de novo methylated in all lymphoma subtypes studied and 22 methylated in a lymphoma subtype-specific manner. Remarkably, the group of genes de novo methylated in all lymphoma subtypes was significantly enriched for polycomb targets in embryonic stem cells. De novo methylated genes in all maB-NHLs studied were expressed at low levels in lymphomas and normal hematopoietic tissues but not in nonhematopoietic tissues. These findings, especially the enrichment for polycomb targets in stem cells, indicate that maB-NHLs with different morphologic, genetic, and transcriptional background share a similar stem cell-like epigenetic pattern. This suggests that maB-NHLs originate from cells with stem cell features or that stemness was acquired during lymphomagenesis by epigenetic remodeling.
authors.affiliation: Institute of Human Genetics, University Hospital Schleswig-Holstein Campus Kiel/Christian-Albrechts University Kiel, Kiel, Germany. jimartin@idibell.org
authors.forename: José I
authors.initials: JI
authors.lastname: Martín-Subero
authors.forename: Markus
authors.initials: M
authors.lastname: Kreuz
authors.forename: Marina
authors.initials: M
authors.lastname: Bibikova
authors.forename: Stefan
authors.initials: S
authors.lastname: Bentink
authors.forename: Ole
authors.initials: O
authors.lastname: Ammerpohl
authors.forename: Eliza
authors.initials: E
authors.lastname: Wickham-Garcia
authors.forename: Maciej
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authors.lastname: Rosolowski
authors.forename: Julia
authors.initials: J
authors.lastname: Richter
authors.forename: Lidia
authors.initials: L
authors.lastname: Lopez-Serra
authors.forename: Esteban
authors.initials: E
authors.lastname: Ballestar
authors.forename: Hilmar
authors.initials: H
authors.lastname: Berger
authors.forename: Xabier
authors.initials: X
authors.lastname: Agirre
authors.forename: Heinz-Wolfram
authors.initials: HW
authors.lastname: Bernd
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Calvanese
authors.forename: Sergio B
authors.initials: SB
authors.lastname: Cogliatti
authors.forename: Hans G
authors.initials: HG
authors.lastname: Drexler
authors.forename: Jian-Bing
authors.initials: JB
authors.lastname: Fan
authors.forename: Mario F
authors.initials: MF
authors.lastname: Fraga
authors.forename: Martin L
authors.initials: ML
authors.lastname: Hansmann
authors.forename: Michael
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authors.lastname: Hummel
authors.forename: Wolfram
authors.initials: W
authors.lastname: Klapper
authors.forename: Bernhard
authors.initials: B
authors.lastname: Korn
authors.forename: Ralf
authors.initials: R
authors.lastname: Küppers
authors.forename: Roderick A F
authors.initials: RA
authors.lastname: Macleod
authors.forename: Peter
authors.initials: P
authors.lastname: Möller
authors.forename: German
authors.initials: G
authors.lastname: Ott
authors.forename: Christiane
authors.initials: C
authors.lastname: Pott
authors.forename: Felipe
authors.initials: F
authors.lastname: Prosper
authors.forename: Andreas
authors.initials: A
authors.lastname: Rosenwald
authors.forename: Carsten
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authors.lastname: Schwaenen
authors.forename: Dirk
authors.initials: D
authors.lastname: Schübeler
authors.forename: Marc
authors.initials: M
authors.lastname: Seifert
authors.forename: Benjamin
authors.initials: B
authors.lastname: Stürzenhofecker
authors.forename: Michael
authors.initials: M
authors.lastname: Weber
authors.forename: Swen
authors.initials: S
authors.lastname: Wessendorf
authors.forename: Markus
authors.initials: M
authors.lastname: Loeffler
authors.forename: Lorenz
authors.initials: L
authors.lastname: Trümper
authors.forename: Harald
authors.initials: H
authors.lastname: Stein
authors.forename: Rainer
authors.initials: R
authors.lastname: Spang
authors.forename: Manel
authors.initials: M
authors.lastname: Esteller
authors.forename: David
authors.initials: D
authors.lastname: Barker
authors.forename: Dirk
authors.initials: D
authors.lastname: Hasenclever
authors.forename: Reiner
authors.initials: R
authors.lastname: Siebert
mesh_terms: D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000473:pathology; D019175:DNA Methylation / Q000502:physiology; D053595:Embryonic Stem Cells / Q000378:metabolism / Q000502:physiology; D044127:Epigenesis, Genetic / Q000502:physiology*; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods; D015972:Gene Expression Regulation, Neoplastic; D023281:Genomics / Q000379:methods*; D006412:Hematopoietic Stem Cells / Q000378:metabolism / Q000502:physiology; D006801:Humans; D016393:Lymphoma, B-Cell / Q000235:genetics* / Q000473:pathology; D008297:Male; D009361:Neoplasm Invasiveness; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D014158:Transcription, Genetic / Q000502:physiology; D014407:Tumor Cells, Cultured