New insights into the biology and origin of mature aggressive B-cell lymphomas by combined epigenomic, genomic, and transcriptional profiling.
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.
Martín-Subero
José I
JI
Institute of Human Genetics, University Hospital Schleswig-Holstein Campus Kiel/Christian-Albrechts University Kiel, Kiel, Germany. jimartin@idibell.org
Kreuz
Markus
M
Bibikova
Marina
M
Bentink
Stefan
S
Ammerpohl
Ole
O
Wickham-Garcia
Eliza
E
Rosolowski
Maciej
M
Richter
Julia
J
Lopez-Serra
Lidia
L
Ballestar
Esteban
E
Berger
Hilmar
H
Agirre
Xabier
X
Bernd
Heinz-Wolfram
HW
Calvanese
Vincenzo
V
Cogliatti
Sergio B
SB
Drexler
Hans G
HG
Fan
Jian-Bing
JB
Fraga
Mario F
MF
Hansmann
Martin L
ML
Hummel
Michael
M
Klapper
Wolfram
W
Korn
Bernhard
B
Küppers
Ralf
R
Macleod
Roderick A F
RA
Möller
Peter
P
Ott
German
G
Pott
Christiane
C
Prosper
Felipe
F
Rosenwald
Andreas
A
Schwaenen
Carsten
C
Schübeler
Dirk
D
Seifert
Marc
M
Stürzenhofecker
Benjamin
B
Weber
Michael
M
Wessendorf
Swen
S
Loeffler
Markus
M
Trümper
Lorenz
L
Stein
Harald
H
Spang
Rainer
R
Esteller
Manel
M
Barker
David
D
Hasenclever
Dirk
D
Siebert
Reiner
R
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