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

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Gong, Chun 
Krupka, Joanna A 
Gao, Jie 
Grigoropoulos, Nicholas F 
Giotopoulos, George  ORCID logo


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.



Burkitt lymphoma, DDX3X, MYC, RNA helicase, germinal center, proteotoxic stress, translation, Adolescent, Adult, Aged, Aged, 80 and over, Animals, B-Lymphocytes, Cell Line, Tumor, Child, Child, Preschool, DEAD-box RNA Helicases, Endoplasmic Reticulum Stress, Female, Gene Expression Regulation, Enzymologic, Gene Expression Regulation, Neoplastic, Humans, Loss of Function Mutation, Lymphoma, B-Cell, Male, Mice, Transgenic, Middle Aged, Minor Histocompatibility Antigens, Neoplasm Proteins, Protein Biosynthesis, Proteome, Proteostasis, Proto-Oncogene Proteins c-myc, Young Adult

Journal Title

Mol Cell

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Elsevier BV
Bloodwise (15022)
Medical Research Council (G19/27)
Medical Research Council (MR/M008584/1)
European Research Council (647685)
Wellcome Trust (203151/Z/16/Z)
MRC (MC_UU_12022/10)
Cancer Research UK (C9685/A25163)
Cancer Research UK (A25117)
National Institute for Health and Care Research (IS-BRC-1215-20014)
Medical Research Council (MR/R009708/1)
Medical Research Council (MC_PC_17230)