NK/T‐CELL LYMPHOMA: WHEN PATIENTS MEET OMICS

Abstract

Natural killer/T-cell lymphoma (NKTCL) is a malignant proliferation of CD56+ and cytoCD3+ lymphocytes, which is prevalent in Asian and South American populations. It is characterized by prominent tissue necrosis and aggressive clinical course, with strong association with Epstein-Barr virus (EBV) infection. The molecular pathogenesis of NKTCL has largely remained elusive. Systemic biology works provide novel insights into the pathogenesis and new biomarkers can be discovered with diagnostic and therapeutic implications. As revealed by comparative genomic hybridization, 6q21 is frequently deleted, thus leading to silencing of the tumor-suppressor genes PRDM1, ATG5, AIM1, FOXO3 and HACE1. Also, NKTCL can be distinguished from normal natural killer cells by gene-expression profiling, which has revealed activation of several oncogenic pathways in NKTCL, including those of NF-kB, mitogen-activated protein kinase (MAPK) and Janus kinase-signal transducer and activator of transcription (JAK-STAT). To clarify the molecular pathogenesis of NKTCL, we identified somatic gene mutations in 25 patients with NKTCL by whole-exome sequencing and confirmed them in an extended validation group of 80 patients by targeted sequencing. Recurrent mutations were most frequently located in the RNA helicase gene DDX3X (21/ 105 subjects, 20.0%), tumor suppressors (TP53 and MGA), JAK-STAT pathway molecules (STAT3 and STAT5B) and epigenetic modifiers (MLL2, ARID1A, EP300 and ASXL3). As compared to wild-type protein, DDX3X mutants exhibited decreased RNA-unwinding activity, loss of suppressive effects on cell-cycle progression in natural killer cells and transcriptional activation of NF-kB and MAPK pathways. Meanwhile, we detected multiple EBV-related sequences in tumor samples of all subjects. How EBV is involved in pathogenesis of NKTCL? Using viral capture sequencing, we found EBV integrated genes mainly involving protein regulation, cell signaling and cellular process. Clinically, patients with DDX3X mutations presented a poor prognosis. After combining international prognostic index (IPI) score with gene-mutation status, we can further stratify subjects with NKTCL treated with CHOP regimen into three groups with distinct prognoses: a low-risk subgroup (IPI 0-1 and WT DDX3X and WT TP53), an intermediate-risk subgroup (IPI 0-1 and mutated DDX3X and mutated TP53; IPI 2-5 and WT DDX3X and WT TP53) and a high-risk subgroup (IPI 2-5 and mutated DDX3X and mutated TP53). Although chemotherapy and radiotherapy are able to improve the disease outcome, the prognosis of NKTCL is generally poor, and no targeted therapy is currently available. Recent studies indicated that L-ASP-based regimen, such as SMILE, AspMetDex and P-GEMOX regimen were efficient in treating NKTCL. Using UPLC-QTOFMS, we identified distinct metabolomic profile in NKTCL and suggested that metabolism-targeted agents were key components. On the other hand, novel targeted agents, such as read-through therapy to DDX3X, JAK inhibitors to JAK/STAT pathway, HDACIs to epigenetic aberrations, and AKT/mTOR inhibitor, may be promising therapeutic strategies in treating NKTCL. In the future, scientific research on NKTCL should be strengthened in China, focusing on EBV-related pathogenesis, prognostic study in the next-generation sequencing era, as well as genetic abnormalities in relapsed/refractory NKTCL. Meanwhile, multi-center clinical trial should be carried out in Asia-Pacific countries, to further obtain the randomized data of L-ASP-based regimens, to finally realize precision medicine and to make NKTCL a curable disease.