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.

Department of Clinical Translational Research Singapore General Hospital Outram Road Singapore 169856 Singapore

Department of Haematology Singapore General Hospital Singapore Singapore

Department of Medicine 2 Hematology Oncology Goethe University Theodor Stern Kai 7 60590 Frankfurt Germany; German Cancer Research Center and German Cancer Consortium Heidelberg Germany; Frankfurt Cancer Institute Goethe University Frankfurt 60596 Frankfurt Germany

Department of Paediatric Oncology Addenbrooke's Hospital Cambridge UK

Division of Cellular and Molecular Pathology Department of Pathology University of Cambridge Cambridge CB20QQ UK

Division of Cellular and Molecular Pathology Department of Pathology University of Cambridge Cambridge CB20QQ UK; CEITEC Masaryk University Brno Czech Republic

Epidemiology and Cancer Statistics Group Department of Health Sciences University of York York YO10 5DD UK

Haematological Malignancy Diagnostic Service St James's Institute of Oncology Leeds LS9 7TF UK

Haematological Malignancy Diagnostic Service St James's Institute of Oncology Leeds LS9 7TF UK; Section of Experimental Haematology Leeds Institute of Molecular Medicine University of Leeds Leeds LS2 9JT UK

Immunology Programme The Babraham Institute Cambridge CB22 3AT UK

MRC Cancer Unit University of Cambridge Hutchison MRC Research Centre Cambridge CB2 0XZ UK

National Horizons Centre Teesside University 38 John Dixon Lane Darlington DL1 1HG UK; School of Health and Life Sciences Teesside University Middlesbrough TS1 3BA UK

National Horizons Centre Teesside University 38 John Dixon Lane Darlington DL1 1HG UK; Wolfson Childhood Cancer Research Centre Northern Institute for Cancer Research Newcastle University Newcastle upon Tyne UK; School of Health and Life Sciences Teesside University Middlesbrough TS1 3BA UK

School of Biological Sciences Nanyang Technological University 60 Nanyang Drive Singapore Singapore

The Francis Crick Institute London NW1 1AT UK; Department for Neuromuscular Diseases UCL Queen Square Institute of Neurology London WC1N 3BG UK

Wellcome MRC Cambridge Stem Cell Institute University of Cambridge Puddicombe Way Cambridge CB2 0AW UK

Wellcome MRC Cambridge Stem Cell Institute University of Cambridge Puddicombe Way Cambridge CB2 0AW UK; Department of Haematology University of Cambridge Cambridge CB2 0AW UK

Wellcome MRC Cambridge Stem Cell Institute University of Cambridge Puddicombe Way Cambridge CB2 0AW UK; Department of Haematology University of Cambridge Cambridge CB2 0AW UK; MRC Cancer Unit University of Cambridge Hutchison MRC Research Centre Cambridge CB2 0XZ UK

Wellcome Trust Sanger Institute Hinxton Cambridge CB10 1SA UK

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