DDX3X Mutation Endow R-Loop-Dependent Lymphomagenesis

RNA helicase DDX3X is generally implicated in inflammasome activation and anti-viral responses. We characterized the common features of scattered DDX3X mutation using molecular dynamic simulation and full-length crystallization, and extended the vital role of DDX3X as a pan-cancer mutation in Epstein-Barr virus (EBV) lytic gene-driven manner. DDX3X mutation was significantly related to impaired STING/IRF-7/IFN-α/β-mediated innate immunity, overexpression of EBV lytic gene BNLF2b, and increased formation of RNA-DNA hybrids R-loops. In Ddx3x449_450ET>DP conditional knock-in transgenic mice, BNLF2b overexpression induced R-loop accumulation, genomic instability, and abnormal proliferation of CD3-/CD19-/NK1.1+ cells, thereby promoting malignant progression. DNA-damaging agent etoposide enhanced γ-H2AX co-localizing with R-loops, heightened genomic instability beyond cellular tolerance, eventually triggering synthetic lethality in DDX3XmutBNLF2b+ tumors. These findings provide better understanding on functional interaction of DDX3X mutation with EBV to provoke R-loop-dependent oncogenesis, shedding new lights on pathogenic mechanism of EBV and future therapeutic approaches targeting R-loops in diseases involving RNA helicase alterations.

No relevant conflicts of interest to declare.