title: DNA methylation dynamics during B cell maturation underlie a continuum of disease phenotypes in chronic lymphocytic leukemia.
abstract: Charting differences between tumors and normal tissue is a mainstay of cancer research. However, clonal tumor expansion from complex normal tissue architectures potentially obscures cancer-specific events, including divergent epigenetic patterns. Using whole-genome bisulfite sequencing of normal B cell subsets, we observed broad epigenetic programming of selective transcription factor binding sites coincident with the degree of B cell maturation. By comparing normal B cells to malignant B cells from 268 patients with chronic lymphocytic leukemia (CLL), we showed that tumors derive largely from a continuum of maturation states reflected in normal developmental stages. Epigenetic maturation in CLL was associated with an indolent gene expression pattern and increasingly favorable clinical outcomes. We further uncovered that most previously reported tumor-specific methylation events are normally present in non-malignant B cells. Instead, we identified a potential pathogenic role for transcription factor dysregulation in CLL, where excess programming by EGR and NFAT with reduced EBF and AP-1 programming imbalances the normal B cell epigenetic program.
authors.affiliation: Division of Epigenomics and Cancer Risk Factors, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Christopher C
authors.initials: CC
authors.lastname: Oakes
authors.affiliation: Institute of Cell Biology (Cancer Research), University of Duisburg-Essen, Essen, Germany.
authors.forename: Marc
authors.initials: M
authors.lastname: Seifert
authors.affiliation: Division of Epigenomics and Cancer Risk Factors, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Yassen
authors.initials: Y
authors.lastname: Assenov
authors.affiliation: Department of Cell Biology, Harvard Medical School, Boston, Massachusetts, USA.|Division of Newborn Medicine, Boston Children's Hospital, Boston, Massachusetts, USA.
authors.forename: Lei
authors.initials: L
authors.lastname: Gu
authors.affiliation: Institute of Cell Biology (Cancer Research), University of Duisburg-Essen, Essen, Germany.
authors.forename: Martina
authors.initials: M
authors.lastname: Przekopowitz
authors.affiliation: Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, Ohio, USA.
authors.forename: Amy S
authors.initials: AS
authors.lastname: Ruppert
authors.affiliation: Division of Theoretical Bioinformatics, German Cancer Research Center (DKFZ), Heidelberg, Germany.|Division of Applied Bioinformatics, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Qi
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Division of Theoretical Bioinformatics, German Cancer Research Center (DKFZ), Heidelberg, Germany.|Division of Applied Bioinformatics, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Charles D
authors.initials: CD
authors.lastname: Imbusch
authors.affiliation: Division of Molecular Genetics, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Andrius
authors.initials: A
authors.lastname: Serva
authors.affiliation: Division of Theoretical Bioinformatics, German Cancer Research Center (DKFZ), Heidelberg, Germany.|Division of Applied Bioinformatics, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Sandra D
authors.initials: SD
authors.lastname: Koser
authors.affiliation: Division of Epigenomics and Cancer Risk Factors, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: David
authors.initials: D
authors.lastname: Brocks
authors.affiliation: Division of Epigenomics and Cancer Risk Factors, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Daniel B
authors.initials: DB
authors.lastname: Lipka
authors.affiliation: Division of Epigenomics and Cancer Risk Factors, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Olga
authors.initials: O
authors.lastname: Bogatyrova
authors.affiliation: Division of Epigenomics and Cancer Risk Factors, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Dieter
authors.initials: D
authors.lastname: Weichenhan
authors.affiliation: Division of Theoretical Bioinformatics, German Cancer Research Center (DKFZ), Heidelberg, Germany.|Division of Applied Bioinformatics, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Benedikt
authors.initials: B
authors.lastname: Brors
authors.affiliation: Department of Medicine, University of California at San Diego Moores Cancer Center, La Jolla, California, USA.
authors.forename: Laura
authors.initials: L
authors.lastname: Rassenti
authors.affiliation: Department of Medicine, University of California at San Diego Moores Cancer Center, La Jolla, California, USA.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Kipps
authors.affiliation: Cooperation Unit Mechanisms of Leukemogenesis, German Cancer Research Center (DKFZ), Heidelberg, Germany.|Department of Internal Medicine III, University of Ulm, Ulm, Germany.
authors.forename: Daniel
authors.initials: D
authors.lastname: Mertens
authors.affiliation: Division of Molecular Genetics, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Marc
authors.initials: M
authors.lastname: Zapatka
authors.affiliation: Division of Molecular Genetics, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Lichter
authors.affiliation: Department of Internal Medicine III, University of Ulm, Ulm, Germany.
authors.forename: Hartmut
authors.initials: H
authors.lastname: Döhner
authors.affiliation: Institute of Cell Biology (Cancer Research), University of Duisburg-Essen, Essen, Germany.
authors.forename: Ralf
authors.initials: R
authors.lastname: Küppers
authors.affiliation: Department of Translational Oncology, National Center for Tumor Diseases (NCT) and German Cancer Research Center (DKFZ), Heidelberg, Germany.|Department of Medicine V, University of Heidelberg, Heidelberg, Germany.
authors.forename: Thorsten
authors.initials: T
authors.lastname: Zenz
authors.affiliation: Cooperation Unit Mechanisms of Leukemogenesis, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Stephan
authors.initials: S
authors.lastname: Stilgenbauer
authors.affiliation: Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, Ohio, USA.
authors.forename: John C
authors.initials: JC
authors.lastname: Byrd
authors.affiliation: Division of Epigenomics and Cancer Risk Factors, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Christoph
authors.identifier: http://orcid.org/0000-0003-2554-3952
authors.initials: C
authors.lastname: Plass
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism*; D001665:Binding Sites; D018899:CpG Islands / Q000235:genetics; D019175:DNA Methylation / Q000235:genetics*; D044127:Epigenesis, Genetic; D005260:Female; D015973:Gene Expression Regulation, Leukemic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics; D010641:Phenotype; D011401:Promoter Regions, Genetic
chemical_list: D009363:Neoplasm Proteins