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Insights into the Pathogenesis of Anaplastic Large-Cell Lymphoma through Genome-wide DNA Methylation Profiling.

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Hassler, Melanie R 
Pulverer, Walter 
Lakshminarasimhan, Ranjani 
Redl, Elisa 
Hacker, Julia 


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.



DNA methylation, NPM-ALK, anaplastic large-cell lymphoma, Adolescent, Adult, Aged, Cell Differentiation, Cell Line, Tumor, Child, DNA Methylation, Female, Genome, Human, Humans, Lymphocyte Activation, Lymphoma, Large-Cell, Anaplastic, Male, Middle Aged, Protein-Tyrosine Kinases, Signal Transduction, Young Adult

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Elsevier BV
Leukaemia & Lymphoma Research (12065)
University of Ha'il (UoH) (unknown)
European Commission Horizon 2020 (H2020) Marie Sk?odowska-Curie actions (675712)
G.E. was funded by the Austrian Science Foundation (FWF) (P 27616 and V 102). M.R.H. was supported by a L’Oréal for Women in Science grant. S.D.T. receives funding from Bloodwise (formerly Leukaemia and Lymphoma Research). L.K. has been funded by the FWF (P 26011 and P 29251), as well as the MSCA-ITN-2015-ETN ALKATRAS (No. 675712). D.J.W. is a paid consultant for Zymo Research Corporation.