No conflicts of interest were declared.
Activated oncogenic pathways and therapeutic targets in extranodal nasal-type NK/T cell lymphoma revealed by gene expression profiling†
Version of Record online: 5 JAN 2011
Copyright © 2011 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
The Journal of Pathology
Volume 223, Issue 4, pages 496–510, March 2011
How to Cite
Ng, S.-B., Selvarajan, V., Huang, G., Zhou, J., Feldman, A. L., Law, M., Kwong, Y.-L., Shimizu, N., Kagami, Y., Aozasa, K., Salto-Tellez, M. and Chng, W.-J. (2011), Activated oncogenic pathways and therapeutic targets in extranodal nasal-type NK/T cell lymphoma revealed by gene expression profiling. J. Pathol., 223: 496–510. doi: 10.1002/path.2823
- Issue online: 3 FEB 2011
- Version of Record online: 5 JAN 2011
- Accepted manuscript online: 18 NOV 2010 09:53AM EST
- Manuscript Accepted: 4 NOV 2010
- Manuscript Revised: 3 NOV 2010
- Manuscript Received: 9 SEP 2010
- NMRC Clinician Scientist Investigator award
- National University of Singapore. Grant Number: R-179-000-040-133
- Singapore Cancer Syndicate. Grant Number: SCS-GRN102
- Singapore National Research Foundation
- Ministry of Education under the Research Centre of Excellence Programme
- NK/T-cell lymphoma;
- gene expression profiling;
- paraffin-embedded tissue
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. Copyright © 2011 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.