The Genomics and Molecular Biology of Natural Killer/T-Cell Lymphoma: Opportunities for Translation

Int J Mol Sci. 2018 Jun 30;19(7):1931. doi: 10.3390/ijms19071931.

Abstract

Extranodal NK/T-cell lymphoma, nasal type (ENKTL), is an aggressive malignancy with a poor prognosis. While the introduction of L-asparaginase in the treatment of this disease has significantly improved the prognosis, the outcome of patients relapsing after asparaginase-based chemotherapy, which occurs in up to 50% of patients with disseminated disease, remains dismal. There is hence an urgent need for effective targeted therapy especially in the relapsed/refractory setting. Gene expression profiling studies have provided new perspectives on the molecular biology, ontogeny and classification of ENKTL and further identified dysregulated signaling pathways such as Janus associated kinase (/Signal Transducer and activation of transcription (JAK/STAT), Platelet derived growth factor (PDGF), Aurora Kinase and NF-κB, which are under evaluation as therapeutic targets. Copy number analyses have highlighted potential tumor suppressor genes such as PR Domain Zinc Finger Protein 1 (PRDM1) and protein tyrosine phosphatase kappa (PTPRK) while next generation sequencing studies have identified recurrently mutated genes in pro-survival and anti-apoptotic pathways. The discovery of epigenetic dysregulation and aberrant microRNA activity has broadened our understanding of the biology of ENKTL. Importantly, immunotherapy via Programmed Cell Death -1 (PD-1) and Programmed Cell Death Ligand1 (PD-L1) checkpoint signaling inhibition is emerging as an attractive therapeutic strategy in ENKTL. Herein, we present an overview of the molecular biology and genomic landscape of ENKTL with a focus on the most promising translational opportunities.

Keywords: Gene expression profiling (GEP); NK/T-cell lymphoma; copy number; epigenetics; genomics; immune checkpoint; targeted therapy.

Publication types

  • Review

MeSH terms

  • Animals
  • DNA Copy Number Variations / genetics
  • Epigenomics / methods
  • Gene Expression Profiling / methods
  • Genomics / methods*
  • Humans
  • Lymphoma, Extranodal NK-T-Cell / genetics*
  • Lymphoma, Extranodal NK-T-Cell / metabolism*
  • Platelet-Derived Growth Factor / metabolism
  • Protein Tyrosine Phosphatases / metabolism

Substances

  • Platelet-Derived Growth Factor
  • Protein Tyrosine Phosphatases