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Nat Genet. 2016 Mar;48(3):253-64. doi: 10.1038/ng.3488. Epub 2016 Jan 18.

DNA methylation dynamics during B cell maturation underlie a continuum of disease phenotypes in chronic lymphocytic leukemia.

Author information

1
Division of Epigenomics and Cancer Risk Factors, German Cancer Research Center (DKFZ), Heidelberg, Germany.
2
Institute of Cell Biology (Cancer Research), University of Duisburg-Essen, Essen, Germany.
3
Department of Cell Biology, Harvard Medical School, Boston, Massachusetts, USA.
4
Division of Newborn Medicine, Boston Children's Hospital, Boston, Massachusetts, USA.
5
Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, Ohio, USA.
6
Division of Theoretical Bioinformatics, German Cancer Research Center (DKFZ), Heidelberg, Germany.
7
Division of Applied Bioinformatics, German Cancer Research Center (DKFZ), Heidelberg, Germany.
8
Division of Molecular Genetics, German Cancer Research Center (DKFZ), Heidelberg, Germany.
9
Department of Medicine, University of California at San Diego Moores Cancer Center, La Jolla, California, USA.
10
Cooperation Unit Mechanisms of Leukemogenesis, German Cancer Research Center (DKFZ), Heidelberg, Germany.
11
Department of Internal Medicine III, University of Ulm, Ulm, Germany.
12
Department of Translational Oncology, National Center for Tumor Diseases (NCT) and German Cancer Research Center (DKFZ), Heidelberg, Germany.
13
Department of Medicine V, University of Heidelberg, Heidelberg, Germany.

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.

PMID:
26780610
PMCID:
PMC4963005
DOI:
10.1038/ng.3488
[Indexed for MEDLINE]
Free PMC Article

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