Exome sequencing identifies somatic mutations of DDX3X in natural killer/T-cell lymphoma

Zhu Chen, Sai-Juan Chen, Wei-Li Zhao and colleagues identify recurrent loss-of-function mutations in the RNA helicase gene DDX3X in 20% of subjects with natural killer/T-cell lymphoma (NKTCL) in their study. The results suggest that DDX3X acts as a tumor suppressor and that its inactivation leads to poor clinical outcome. Natural killer/T-cell lymphoma (NKTCL) is a malignant proliferation of CD56 + and cytoCD3 + lymphocytes with aggressive clinical course, which is prevalent in Asian and South American populations 1 . The molecular pathogenesis of NKTCL has largely remained elusive. We identified somatic gene mutations in 25 people with NKTCL by whole-exome sequencing and confirmed them in an extended validation group of 80 people 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 NK cells and transcriptional activation of NF-κB and MAPK pathways. Clinically, patients with DDX3X mutations presented a poor prognosis. Our work thus contributes to the understanding of the disease mechanism of NKTCL.