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Natural-killer/T cell lymphoma (NKTCL) is a malignant proliferation of CD56+/cytoCD3+ lymphocytes and constitutes a heterogeneous group of aggressive lymphoma prevalent in Asian and South American populations. NKTCL represents a distinct clinicopathologic entity of non-Hodgkin’s lymphoma, characterized by male predominance, strong association with Epstein-Barr virus (EBV) infection, prominent tissue necrosis and aggressive clinical course. However, molecular pathogenesis of NKTCL remains largely elusive. Here we identified somatic mutations by whole-exome sequencing in 25 NKTCL patients and extended validation through targeted sequencing in an additional 80 cases. Functional experiments including RNA unwinding test, colony forming assay, cell proliferation assay and gene expression profiling were also performed. Overall, 50.5% of NKTCL patients displayed somatic mutations of RNA helicase family, tumor suppressors (TP53 and MGA), and/or epigenetic modifiers (MLL2, ARID1A, EP300 and ASXL3). Recurrent mutations were most frequently discovered in RNA helicase gene DDX3X (21/105 cases, 20.0%). Mutations of DDX3X were seldom overlapped with those of TP53. Functionally, DDX3X mutants exhibited reduced RNA unwinding activity and enhanced cell proliferation. Similar stimulatory effect on cell proliferation was observed in cells transfected with specific siRNA targeting DDX3X. Gene expression profiling revealed an association of DDX3X mutations with activation of NF-kB and MAPK pathways. The clinical follow-up data showed that DDX3X-mutated patients presented a poor prognosis. Our work suggests the heterogeneity of gene mutational spectrum of NKTCL and provides a potential therapeutic target for relevant cases. Disclosures No relevant conflicts of interest to declare.