title: Insights into the Pathogenesis of Anaplastic Large-Cell Lymphoma through Genome-wide DNA Methylation Profiling.
abstract: 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.
authors.affiliation: Clinical Institute of Pathology, Medical University of Vienna, 1090 Vienna, Austria.
authors.forename: Melanie R
authors.initials: MR
authors.lastname: Hassler
authors.affiliation: Health & Environment Department, Molecular Diagnostics, Austrian Institute of Technology (AIT), 1190 Vienna, Austria.
authors.forename: Walter
authors.initials: W
authors.lastname: Pulverer
authors.affiliation: Department of Urology, Norris Comprehensive Cancer Center, University of Southern California-Los Angeles, Los Angeles, CA 90089, USA.
authors.forename: Ranjani
authors.initials: R
authors.lastname: Lakshminarasimhan
authors.affiliation: Clinical Institute of Pathology, Medical University of Vienna, 1090 Vienna, Austria.
authors.forename: Elisa
authors.initials: E
authors.lastname: Redl
authors.affiliation: Clinical Institute of Pathology, Medical University of Vienna, 1090 Vienna, Austria.
authors.forename: Julia
authors.initials: J
authors.lastname: Hacker
authors.affiliation: Division of Molecular Histopathology, Department of Pathology, University of Cambridge, Cambridge CB2 0QQ, UK.
authors.forename: Gavin D
authors.initials: GD
authors.lastname: Garland
authors.affiliation: Clinical Institute of Pathology, Medical University of Vienna, 1090 Vienna, Austria; European Research Initiative on ALK-Related Malignancies (ERIA), Cambridge CB2 0QQ, UK.
authors.forename: Olaf
authors.initials: O
authors.lastname: Merkel
authors.affiliation: Clinical Institute of Pathology, Medical University of Vienna, 1090 Vienna, Austria.
authors.forename: Ana-Iris
authors.initials: AI
authors.lastname: Schiefer
authors.affiliation: Clinical Institute of Pathology, Medical University of Vienna, 1090 Vienna, Austria.
authors.forename: Ingrid
authors.initials: I
authors.lastname: Simonitsch-Klupp
authors.affiliation: Clinical Institute of Pathology, Medical University of Vienna, 1090 Vienna, Austria; Ludwig Boltzmann Institute for Cancer Research, 1090 Vienna, Austria; Unit of Pathology of Laboratory Animals (UPLA), University of Veterinary Medicine Vienna, 1210 Vienna, Austria; European Research Initiative on ALK-Related Malignancies (ERIA), Cambridge CB2 0QQ, UK.
authors.forename: Lukas
authors.initials: L
authors.lastname: Kenner
authors.affiliation: Department of Biochemistry and Molecular Biology, Norris Comprehensive Cancer Center, University of Southern California-Los Angeles, Los Angeles, CA 90089, USA.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Weisenberger
authors.affiliation: Health & Environment Department, Molecular Diagnostics, Austrian Institute of Technology (AIT), 1190 Vienna, Austria.
authors.forename: Andreas
authors.initials: A
authors.lastname: Weinhaeusel
authors.affiliation: Division of Molecular Histopathology, Department of Pathology, University of Cambridge, Cambridge CB2 0QQ, UK; European Research Initiative on ALK-Related Malignancies (ERIA), Cambridge CB2 0QQ, UK.
authors.forename: Suzanne D
authors.initials: SD
authors.lastname: Turner
authors.affiliation: Clinical Institute of Pathology, Medical University of Vienna, 1090 Vienna, Austria; European Research Initiative on ALK-Related Malignancies (ERIA), Cambridge CB2 0QQ, UK. Electronic address: gerda.egger@meduniwien.ac.at.
authors.forename: Gerda
authors.initials: G
authors.lastname: Egger
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D002454:Cell Differentiation / Q000235:genetics; D045744:Cell Line, Tumor; D002648:Child; D019175:DNA Methylation / Q000235:genetics*; D005260:Female; D015894:Genome, Human / Q000235:genetics*; D006801:Humans; D008213:Lymphocyte Activation / Q000235:genetics; D017728:Lymphoma, Large-Cell, Anaplastic / Q000235:genetics* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D011505:Protein-Tyrosine Kinases / Q000235:genetics*; D015398:Signal Transduction; D055815:Young Adult
chemical_list: C107023:p80(NPM-ALK) protein; D011505:Protein-Tyrosine Kinases
keywords: DNA methylation; NPM-ALK; anaplastic large-cell lymphoma