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

Cell Rep. 2016 Oct 4;17(2):596-608. doi: 10.1016/j.celrep.2016.09.018.


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.

Keywords: DNA methylation; NPM-ALK; anaplastic large-cell lymphoma.

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Cell Differentiation / genetics
  • Cell Line, Tumor
  • Child
  • DNA Methylation / genetics*
  • Female
  • Genome, Human / genetics*
  • Humans
  • Lymphocyte Activation / genetics
  • Lymphoma, Large-Cell, Anaplastic / genetics*
  • Lymphoma, Large-Cell, Anaplastic / pathology
  • Male
  • Middle Aged
  • Protein-Tyrosine Kinases / genetics*
  • Signal Transduction
  • Young Adult


  • p80(NPM-ALK) protein
  • Protein-Tyrosine Kinases