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

Chun Gong, Joanna A Krupka, Jie Gao, Nicholas F Grigoropoulos, George Giotopoulos, Ryan Asby, Michael Screen, Zelvera Usheva, Francesco Cucco, Sharon Barrans, Daniel Painter, Nurmahirah Binte Mohammed Zaini, Björn Haupl, Susanne Bornelöv, Igor Ruiz De Los Mozos, Wei Meng, Peixun Zhou, Alex E Blain, Sorcha Forde, Jamie MatthewsMichelle Guet Khim Tan, 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 Samarajiwa, Daniel J Hodson

Research output: Contribution to journalArticlepeer-review


Summary 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.
Original languageEnglish
Pages (from-to)4059-4075
Number of pages17
JournalMolecular Cell
Issue number19
Publication statusPublished - 7 Oct 2021

Bibliographical note

Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.


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

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