DDX3X is a ubiquitously expressed RNA helicase involved in multiple stages of RNA biogenesis. DDX3X is frequently mutated in Burkitt lymphoma, but the functional basis for this is unknown. Here, we show that loss-of-function DDX3X mutations are also enriched in MYC-translocated diffuse large B cell lymphoma and reveal functional cooperation between mutant DDX3X and MYC. DDX3X promotes the translation of mRNA encoding components of the core translational machinery, thereby driving global protein synthesis. Loss-of-function DDX3X mutations moderate MYC-driven global protein synthesis, thereby buffering MYC-induced proteotoxic stress during early lymphomagenesis. Established lymphoma cells restore full protein synthetic capacity by aberrant expression of DDX3Y, a Y chromosome homolog, the expression of which is normally restricted to the testis. These findings show that DDX3X loss of function can buffer MYC-driven proteotoxic stress and highlight the capacity of male B cell lymphomas to then compensate for this loss by ectopic DDX3Y expression.

• MeSH
• Lymphoma, B-Cell enzymology   genetics   pathology   MeSH
• B-Lymphocytes enzymology   pathology   MeSH
• DEAD-box RNA Helicases genetics   metabolism   MeSH
• Child MeSH
• Adult MeSH
• Proteostasis MeSH
• Middle Aged MeSH
• Humans MeSH
• Adolescent MeSH
• Young Adult MeSH
• Loss of Function Mutation MeSH
• Mice, Transgenic MeSH
• Cell Line, Tumor MeSH
• Neoplasm Proteins biosynthesis   genetics   MeSH
• Child, Preschool MeSH
• Proteome MeSH
• Protein Biosynthesis MeSH
• Proto-Oncogene Proteins c-myc genetics   metabolism   MeSH
• Gene Expression Regulation, Enzymologic MeSH
• Gene Expression Regulation, Neoplastic MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Endoplasmic Reticulum Stress MeSH
• Minor Histocompatibility Antigens genetics   metabolism   MeSH
• Animals MeSH
• Check Tag
• Child MeSH
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Adolescent MeSH
• Young Adult MeSH
• Male MeSH
• Child, Preschool MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Female MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH