title: Activated oncogenic pathways and therapeutic targets in extranodal nasal-type NK/T cell lymphoma revealed by gene expression profiling.
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.
authors.affiliation: Department of Pathology, National University Health System, Singapore. patnsb@nus.edu.sg
authors.forename: Siok-Bian
authors.initials: SB
authors.lastname: Ng
authors.forename: Viknesvaran
authors.initials: V
authors.lastname: Selvarajan
authors.forename: Gaofeng
authors.initials: G
authors.lastname: Huang
authors.forename: Jianbiao
authors.initials: J
authors.lastname: Zhou
authors.forename: Andrew L
authors.initials: AL
authors.lastname: Feldman
authors.forename: Mark
authors.initials: M
authors.lastname: Law
authors.forename: Yok-Lam
authors.initials: YL
authors.lastname: Kwong
authors.forename: Norio
authors.initials: N
authors.lastname: Shimizu
authors.forename: Yoshitoyo
authors.initials: Y
authors.lastname: Kagami
authors.forename: Katsuyuki
authors.initials: K
authors.lastname: Aozasa
authors.forename: Manuel
authors.initials: M
authors.lastname: Salto-Tellez
authors.forename: Wee-Joo
authors.initials: WJ
authors.lastname: Chng
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D017209:Apoptosis / Q000187:drug effects; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods; D053263:Gene Regulatory Networks; D055106:Genome-Wide Association Study; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D007694:Killer Cells, Natural / Q000378:metabolism; D054391:Lymphoma, Extranodal NK-T-Cell / Q000235:genetics* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008297:Male; D009637:Masoprocol / Q000031:analogs & derivatives / Q000494:pharmacology; D008869:Microtubule-Associated Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology; D008875:Middle Aged; D016328:NF-kappa B / Q000378:metabolism; D009363:Neoplasm Proteins / Q000378:metabolism; D009669:Nose Neoplasms / Q000235:genetics* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D009857:Oncogenes / Q000502:physiology*; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D000077022:Survivin; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D055815:Young Adult
chemical_list: C107489:BIRC5 protein, human; D051034:Inhibitor of Apoptosis Proteins; C489427:MYC protein, human; D008869:Microtubule-Associated Proteins; D016328:NF-kappa B; D009363:Neoplasm Proteins; D016271:Proto-Oncogene Proteins c-myc; D000077022:Survivin; D016159:Tumor Suppressor Protein p53; C076852:terameprocol; D009637:Masoprocol