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.

DDX3X 是一种普遍表达的 RNA 解旋酶，参与 RNA 生物发生的多个阶段。DDX3X在伯基特淋巴瘤中经常发生突变，但其功能基础尚不清楚。在这里，我们发现功能丧失的DDX3X突变也在MYC易位的弥漫性大 B 细胞淋巴瘤中富集，并揭示了突变型 DDX3X 和 MYC 之间的功能合作。DDX3X 促进核心翻译机制的 mRNA 编码组件的翻译，从而驱动整体蛋白质合成。功能丧失的 DDX3X 突变可调节 MYC 驱动的整体蛋白质合成，从而缓冲早期淋巴瘤发生过程中 MYC 诱导的蛋白毒性应激。建立的淋巴瘤细胞通过 DDX3Y（一种 Y 染色体同源物）的异常表达来恢复全部蛋白质合成能力，其表达通常仅限于睾丸。这些发现表明，DDX3X 功能丧失可以缓冲 MYC 驱动的蛋白毒性应激，并强调男性 B 细胞淋巴瘤通过异位 DDX3Y 表达补偿这种功能丧失的能力。