DDX3X mutation and Epstein-Barr virus cooperate to induce R-loop-dependent oncogenesis

Area of Science:

• Oncology
• Virology
• Molecular Biology

Background:

• RNA helicase DDX3X is involved in inflammasome activation and antiviral responses.
• Scattered DDX3X mutations are observed in lymphoid cancers.
• Epstein-Barr virus (EBV) plays a role in oncogenesis.

Purpose of the Study:

• To characterize common features of DDX3X mutations in lymphoid cancers.
• To elucidate the role of DDX3X mutations in EBV-driven oncogenesis.
• To investigate the functional interaction between DDX3X mutations and EBV.

Main Methods:

• Molecular dynamics simulation and crystallization were used to study DDX3X mutations.
• Conditional knockin transgenic mice (Ddx3x^449_450ET>DP) were utilized.
• The effects of etoposide on DDX3X mutant tumors were examined.

Main Results:

• DDX3X mutations impair STING/IRF-7/IFN-α/β-mediated innate immunity.
• Mutations lead to overexpression of EBV lytic gene BNLF2b and increased R-loop formation.
• BNLF2b expression in mice induces R-loop accumulation, genomic instability, and abnormal immune cell proliferation, promoting malignancy.
• Etoposide treatment triggers synthetic lethality in DDX3X mutant BNLF2b positive tumors.

Conclusions:

• DDX3X mutations interact with EBV to drive R-loop-dependent oncogenesis.
• Findings illuminate EBV's pathogenic mechanism and suggest R-loop targeting therapies.
• This research provides insights into diseases involving RNA helicase alterations.