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

Siok Bian Ng, Viknesvaran Selvarajan, Gaofeng Huang, Jianbiao Zhou, Andrew L. Feldman, Mark Law, Yok Lam Kwong, Norio Shimizu, Yoshitoyo Kagami, Katsuyuki Aozasa, Manuel Salto-Tellez, Wee Joo Chng

Research output: Contribution to journalArticlepeer-review

98 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)496-510
Number of pages15
JournalJournal of Pathology
Volume223
Issue number4
DOIs
StatePublished - Mar 2011

Keywords

  • Myc
  • NF-κB
  • NK/T-cell lymphoma
  • gene expression profiling
  • p53
  • paraffin-embedded tissue
  • survivin

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

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