Activated oncogenic pathways and therapeutic targets in extranodal nasal-type NK/T cell lymphoma revealed by gene expression profiling

J Pathol. 2011 Mar;223(4):496-510. doi: 10.1002/path.2823. Epub 2011 Jan 5.


We performed comprehensive genome-wide gene expression profiling (GEP) of extranodal nasal-type natural killer/T-cell lymphoma (NKTL) using formalin-fixed, paraffin-embedded tissue (n = 9) and NK cell lines (n = 5) in comparison with normal NK cells, with the objective of understanding the oncogenic pathways involved in the pathogenesis of NKTL and to identify potential therapeutic targets. Pathway and network analysis of genes differentially expressed between NKTL and normal NK cells revealed significant enrichment for cell cycle-related genes and pathways, such as PLK1, CDK1, and Aurora-A. Furthermore, our results demonstrated a pro-proliferative and anti-apoptotic phenotype in NKTL characterized by activation of Myc and nuclear factor kappa B (NF-κB), and deregulation of p53. In corroboration with GEP findings, a significant percentage of NKTLs (n = 33) overexpressed c-Myc (45.4%), p53 (87.9%), and NF-κB p50 (67.7%) on immunohistochemistry using a tissue microarray containing 33 NKTL samples. Notably, overexpression of survivin was observed in 97% of cases. Based on our findings, we propose a model of NKTL pathogenesis where deregulation of p53 together with activation of Myc and NF-κB, possibly driven by EBV LMP-1, results in the cumulative up-regulation of survivin. Down-regulation of survivin with Terameprocol (EM-1421, a survivin inhibitor) results in reduced cell viability and increased apoptosis in tumour cells, suggesting that targeting survivin may be a potential novel therapeutic strategy in NKTL.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Aged, 80 and over
  • Apoptosis / drug effects
  • Female
  • Gene Expression Profiling / methods
  • Gene Regulatory Networks
  • Genome-Wide Association Study
  • Humans
  • Inhibitor of Apoptosis Proteins
  • Killer Cells, Natural / metabolism
  • Lymphoma, Extranodal NK-T-Cell / genetics*
  • Lymphoma, Extranodal NK-T-Cell / immunology
  • Lymphoma, Extranodal NK-T-Cell / metabolism
  • Lymphoma, Extranodal NK-T-Cell / pathology
  • Male
  • Masoprocol / analogs & derivatives
  • Masoprocol / pharmacology
  • Microtubule-Associated Proteins / antagonists & inhibitors
  • Microtubule-Associated Proteins / metabolism
  • Microtubule-Associated Proteins / physiology
  • Middle Aged
  • NF-kappa B / metabolism
  • Neoplasm Proteins / metabolism
  • Nose Neoplasms / genetics*
  • Nose Neoplasms / immunology
  • Nose Neoplasms / metabolism
  • Nose Neoplasms / pathology
  • Oncogenes / physiology*
  • Proto-Oncogene Proteins c-myc / metabolism
  • Survivin
  • Tumor Cells, Cultured
  • Tumor Suppressor Protein p53 / metabolism
  • Young Adult


  • BIRC5 protein, human
  • Inhibitor of Apoptosis Proteins
  • MYC protein, human
  • Microtubule-Associated Proteins
  • NF-kappa B
  • Neoplasm Proteins
  • Proto-Oncogene Proteins c-myc
  • Survivin
  • Tumor Suppressor Protein p53
  • terameprocol
  • Masoprocol