Sequential inverse dysregulation of the RNA helicases DDX3X and DDX3Y facilitates MYC-driven lymphomagenesis

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. [Display omitted] •Loss-of-function mutations of DDX3X are frequent in MYC-driven B cell lymphomas•DDX3X promotes translation of mRNAs encoding the core protein synthesis machinery•Loss of DDX3X buffers MYC-driven global protein synthesis and proteotoxic stress•DDX3X loss is later rescued by ectopic expression of Y-chromosome-encoded DDX3Y Gong et al. show that during the early stages of lymphoma development, loss-of-function mutations in the RNA helicase DDX3X allow human B cells to tolerate the forced expression of MYC. In contrast, established tumors restore DDX3 helicase activity by ectopic expression of the Y-chromosome-encoded homolog DDX3Y.