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

doi:10.1016/j.celrep.2016.09.018

Abstract

SummaryAberrant 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.

Highlights

Anaplastic large-cell lymphoma (ALCL) is a category of nonHodgkin lymphoma (NHL) and is of T cell origin
After data normalization and quality control steps, we identified 42,752 and 12,354 significant methylation variable positions (MVPs) between tumor (ALK+ or ALKÀ) and normal control (CD3+ T cells) (Figure 1A)
MVPs differentiating between ALKÀ and T cells (5,453 probes) showed similar methylation in anaplastic lymphoma kinase (ALK)+ ALCL (Figure 1C)

Summary

Introduction

Anaplastic large-cell lymphoma (ALCL) is a category of nonHodgkin lymphoma (NHL) and is of T cell origin. A specific translocation (t(2;5)(p23q35)) involving fusion of the ubiquitously expressed nucleolar shuttling protein Nucleophosmin (NPM1) to the receptor tyrosine kinase anaplastic lymphoma kinase (ALK) is detected in more than 30% of ALCL cases (Morris et al, 1994). This translocation leads to the expression of the constitutively active NPM-ALK kinase, which is a potent trigger of multiple signaling pathways and is sufficient to drive cells toward malignant transformation (Bischof et al, 1997; Chiarle et al, 2003; Fujimoto et al, 1996; Turner et al, 2003). ALKÀ ALCL shows a more heterogeneous genome in terms of somatic mutations and fusion transcripts, and gene expression studies indicate that ALK+ ALCL and ALKÀ ALCL display similar signatures, suggesting a common cell of origin (Boi et al, 2015; Eckerle et al, 2009)

Results

Discussion

Conclusion