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

• DOI: 10.1016/j.molcel.2021.07.041
• Publication Date: 2021-08-25T14:26:22Z
• Authors: Chun Gong; Joanna A. Krupka; Jie Gao; Nicholas F. Grigo...; George Giotopoulos; Ryan Asby; Michael Screen; Zelvera Usheva; Francesco Cucco; Sharon Barrans; Daniel Painter; Nurmahirah Binte ...; Björn Haupl; Susanne Bornelöv; Igor Ruiz De Los ...; Wei Meng; Peixun Zhou; Alex E. Blain; Sorcha Forde; Jamie Matthews; Michelle Guet Khi...; G.A. Amos Burke; Siu Kwan Sze; Philip Beer; Cathy Burton; Peter Campbell; Vikki Rand; Suzanne D. Turner; Jernej Ule; Eve Roman; Reuben Tooze; Thomas Oellerich; Brian J. Huntly; Martin Turner; Ming-Qing Du; Shamith A. Samara...; Daniel J. Hodson
• Keywords: 0301 basic medicine; Male; AZFA GENE DDX3Y; Proteome; PROTEIN; Gene Expression; translation; MYC; EEF2 KINASE; DEAD-box RNA Helicases; proteotoxic stress; Ecology,Evolution & Ethology; Loss of Function Mutation; TUMOR-SUPPRESSOR; Child; Aged, 80 and over; B-Lymphocytes; 0303 health sciences; Stem Cells; Burkitt lymphoma; Middle Aged; Endoplasmic Reticulum Stress; READ ALIGNMENT; Neoplasm Proteins; Gene Expression Regulation, Neoplastic; Child, Preschool; DDX3X; Female; MESSENGER-RNA; Life Sciences & Biomedicine; Genetics & Genomics; Adult; Biochemistry & Molecular Biology; RNA helicase; Lymphoma, B-Cell; Adolescent; Mice, Transgenic; Biochemistry & Proteomics; Gene Expression Regulation, Enzymologic; Minor Histocompatibility Antigens; Proto-Oncogene Proteins c-myc; Young Adult; 03 medical and health sciences; Cell Line, Tumor; Animals; Humans; Computational & Systems Biology; Aged; Science & Technology; IDENTIFICATION; MUTATIONS; FOS: Clinical medicine; STRESS GRANULES; Neurosciences; Cell Biology; germinal center; Protein Biosynthesis; Proteostasis; TRANSLATION

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.