Insights into the Pathogenesis of Anaplastic Large-Cell Lymphoma through Genome-wide DNA Methylation Profiling
Melanie R. Hassler,
Walter Pulverer,
Ranjani Lakshminarasimhan,
Elisa Redl,
Julia Hacker,
Gavin D. Garland,
Olaf Merkel,
Ana-Iris Schiefer,
Ingrid Simonitsch-Klupp,
Lukas Kenner,
Daniel J. Weisenberger,
Andreas Weinhaeusel,
Suzanne D. Turner,
Gerda Egger
Affiliations
Melanie R. Hassler
Clinical Institute of Pathology, Medical University of Vienna, 1090 Vienna, Austria
Walter Pulverer
Health & Environment Department, Molecular Diagnostics, Austrian Institute of Technology (AIT), 1190 Vienna, Austria
Ranjani Lakshminarasimhan
Department of Urology, Norris Comprehensive Cancer Center, University of Southern California-Los Angeles, Los Angeles, CA 90089, USA
Elisa Redl
Clinical Institute of Pathology, Medical University of Vienna, 1090 Vienna, Austria
Julia Hacker
Clinical Institute of Pathology, Medical University of Vienna, 1090 Vienna, Austria
Gavin D. Garland
Division of Molecular Histopathology, Department of Pathology, University of Cambridge, Cambridge CB2 0QQ, UK
Olaf Merkel
Clinical Institute of Pathology, Medical University of Vienna, 1090 Vienna, Austria
Ana-Iris Schiefer
Clinical Institute of Pathology, Medical University of Vienna, 1090 Vienna, Austria
Ingrid Simonitsch-Klupp
Clinical Institute of Pathology, Medical University of Vienna, 1090 Vienna, Austria
Lukas Kenner
Clinical Institute of Pathology, Medical University of Vienna, 1090 Vienna, Austria
Daniel J. Weisenberger
Department of Biochemistry and Molecular Biology, Norris Comprehensive Cancer Center, University of Southern California-Los Angeles, Los Angeles, CA 90089, USA
Andreas Weinhaeusel
Health & Environment Department, Molecular Diagnostics, Austrian Institute of Technology (AIT), 1190 Vienna, Austria
Suzanne D. Turner
Division of Molecular Histopathology, Department of Pathology, University of Cambridge, Cambridge CB2 0QQ, UK
Gerda Egger
Clinical Institute of Pathology, Medical University of Vienna, 1090 Vienna, Austria
Aberrant DNA methylation patterns in malignant cells allow insight into tumor evolution and development and can be used for disease classification. Here, we describe the genome-wide DNA methylation signatures of NPM-ALK-positive (ALK+) and NPM-ALK-negative (ALK−) anaplastic large-cell lymphoma (ALCL). We find that ALK+ and ALK− ALCL share common DNA methylation changes for genes involved in T cell differentiation and immune response, including TCR and CTLA-4, without an ALK-specific impact on tumor DNA methylation in gene promoters. Furthermore, we uncover a close relationship between global ALCL DNA methylation patterns and those in distinct thymic developmental stages and observe tumor-specific DNA hypomethylation in regulatory regions that are enriched for conserved transcription factor binding motifs such as AP1. Our results indicate similarity between ALCL tumor cells and thymic T cell subsets and a direct relationship between ALCL oncogenic signaling and DNA methylation through transcription factor induction and occupancy.
