New insights into the biology and origin of mature aggressive B-cell lymphomas by combined epigenomic, genomic, and transcriptional profiling

Author:

Martín-Subero José I.1,Kreuz Markus2,Bibikova Marina3,Bentink Stefan4,Ammerpohl Ole1,Wickham-Garcia Eliza3,Rosolowski Maciej2,Richter Julia1,Lopez-Serra Lidia5,Ballestar Esteban5,Berger Hilmar2,Agirre Xabier6,Bernd Heinz-Wolfram7,Calvanese Vincenzo5,Cogliatti Sergio B.8,Drexler Hans G.9,Fan Jian-Bing3,Fraga Mario F.5,Hansmann Martin L.10,Hummel Michael11,Klapper Wolfram12,Korn Bernhard13,Küppers Ralf14,MacLeod Roderick A. F.9,Möller Peter15,Ott German16,Pott Christiane17,Prosper Felipe6,Rosenwald Andreas16,Schwaenen Carsten18,Schübeler Dirk19,Seifert Marc14,Stürzenhofecker Benjamin20,Weber Michael19,Wessendorf Swen18,Loeffler Markus2,Trümper Lorenz20,Stein Harald11,Spang Rainer4,Esteller Manel5,Barker David3,Hasenclever Dirk2,Siebert Reiner1,

Affiliation:

1. Institute of Human Genetics, University Hospital Schleswig-Holstein Campus Kiel/Christian-Albrechts University Kiel, Kiel, Germany;

2. Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Leipzig, Germany;

3. Illumina, San Diego, CA;

4. Institute of Functional Genomics, University of Regensburg, Regensburg, Germany;

5. Cancer Epigenetics Laboratory, Spanish National Cancer Centre (CNIO), Madrid, Spain;

6. Foundation for Applied Medical Research, Division of Cancer and Area of Cell Therapy and Hematology Service, Clínica Universitaria, Universidad de Navarra, Pamplona, Spain;

7. Institute of Pathology, University Hospital Schleswig-Holstein Campus Lübeck, Lübeck, Germany;

8. Institute of Pathology, Kantonsspital St Gallen, St Gallen, Switzerland;

9. DSMZ-German Collection of Microorganisms and Cell Cultures, Braunschweig, Germany;

10. Institute of Pathology, University Hospital of Frankfurt, Frankfurt, Germany;

11. Institute of Pathology, Campus Benjamin Franklin, Charité-Universitätsmedizin Berlin, Berlin, Germany;

12. Institute of Hematopathology, University Hospital Schleswig-Holstein Campus Kiel/Christian-Albrechts University Kiel, Kiel, Germany;

13. Genomics and Proteomics Core Facility, German Cancer Research Center, Heidelberg, Germany;

14. Institute for Cell Biology (Tumor Research), University of Duisburg-Essen, Essen, Germany;

15. Institute of Pathology, University Hospital of Ulm, Ulm, Germany;

16. Institute of Pathology, University of Würzburg, Würzburg, Germany;

17. Second Medical Department, University Hospital Schleswig-Holstein Campus Kiel/Christian-Albrechts University Kiel, Kiel, Germany;

18. Cytogenetic and Molecular Diagnostics, Internal Medicine III, University Hospital of Ulm, Ulm, Germany;

19. Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland; and

20. Department of Hematology and Oncology, Georg-August University of Göttingen, Göttingen, Germany

Abstract

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.

Publisher

American Society of Hematology

Subject

Cell Biology,Hematology,Immunology,Biochemistry

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