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Sequential Inverse Dysregulation of the RNA Helicases DDX3X and DDX3Y Facilitates MYC-Driven Lymphomagenesis

68 Pages Posted: 21 Jan 2020 Publication Status: Review Complete

See all articles by Chun Gong

Chun Gong

Wellcome Trust and MRC Cambridge Stem Cell Institute

Joanna Krupka

Wellcome Trust and MRC Cambridge Stem Cell Institute

Jie Gao

Wellcome Trust and MRC Cambridge Stem Cell Institute

Nicholas Francis Grigoropoulos

Singapore General Hospital - Department of Haematology

Michael Screen

The Babraham Institute

Zelvera Usheva

Wellcome Trust and MRC Cambridge Stem Cell Institute

Francesco Cucco

University of Cambridge - Division of Cellular and Molecular Pathology

Sharon Barrans

St. James’s Institute of Oncology - Haematological Malignancy Diagnostic Service

Daniel Painter

University of York - Epidemiology and Cancer Statistics Group

Mahirah Mohammed

Singapore General Hospital - Department of Haematology

Björn Haupl

Goethe University Frankfurt - Department of Medicine II, Hematology/Oncology

Susanne Bornelöv

Wellcome Trust and MRC Cambridge Stem Cell Institute

Igor Mozos

Francis Crick Institute

Wei Meng

Nanyang Technological University (NTU) - School of Biological Sciences

Peixun Zhou

Teesside University - School of Health & Life Sciences

Alex Blain

Teesside University - School of Health & Life Sciences

Sorcha Forde

University of Cambridge - Division of Cellular and Molecular Pathology

Jamie Matthews

University of Cambridge - Division of Cellular and Molecular Pathology

Michelle Guet Khim Tan

Singapore General Hospital - Department of Clinical Translational Research

G.A. Amos Burke

Addenbrooke’s Hospital - Department of Paediatric Oncology

Siu Kwan Sze

Nanyang Technological University (NTU) - School of Biological Sciences

Philip Beer

Wellcome Trust Sanger Institute

Cathy Burton

St. James’s Institute of Oncology - Haematological Malignancy Diagnostic Service

Peter J. Campbell

Wellcome Genome Campus - Cancer Genome Project; Wellcome Trust Sanger Institute

Vikki Rand

Teesside University - School of Health & Life Sciences

Suzanne Turner

University of Cambridge - Division of Cellular and Molecular Pathology

Jernej Ule

University of Cambridge - MRC Laboratory of Molecular Biology; Francis Crick Institute

Eve Roman

University of York - Epidemiology and Cancer Statistics Group

Reuben Tooze

St. James’s Institute of Oncology - Haematological Malignancy Diagnostic Service

Thomas Oellerich

Goethe University Frankfurt - Department of Medicine II, Hematology/Oncology

Martin Turner

The Babraham Institute

Ming-Qing Du

University of Cambridge - Division of Cellular and Molecular Pathology

Shamith Samarajiwa

University of Cambridge - MRC Cancer Unit

Daniel Hodson

Wellcome Trust and MRC Cambridge Stem Cell Institute

More...

Abstract

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 commonly found in MYC-translocated diffuse large B cell lymphoma and reveal functional co-operation between mutant DDX3X and MYC. DDX3X promotes translation of mRNAs 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 subsequently restore full protein synthetic capacity by aberrant expression of DDX3Y, a Y-chromosome homologue that is normally expressed exclusively in 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 later compensate for this loss by ectopic DDX3Y expression.

Keywords: Lymphoma, Translation, Cancer, MYCDDX3X

Suggested Citation

Gong, Chun and Krupka, Joanna and Gao, Jie and Grigoropoulos, Nicholas Francis and Screen, Michael and Usheva, Zelvera and Cucco, Francesco and Barrans, Sharon and Painter, Daniel and Mohammed, Mahirah and Haupl, Björn and Bornelöv, Susanne and Mozos, Igor and Meng, Wei and Zhou, Peixun and Blain, Alex and Forde, Sorcha and Matthews, Jamie and Tan, Michelle Guet Khim and Burke, G.A. Amos and Sze, Siu Kwan and Beer, Philip and Burton, Cathy and Campbell, Peter J. and Rand, Vikki and Turner, Suzanne and Ule, Jernej and Roman, Eve and Tooze, Reuben and Oellerich, Thomas and Turner, Martin and Du, Ming-Qing and Samarajiwa, Shamith and Hodson, Daniel, Sequential Inverse Dysregulation of the RNA Helicases DDX3X and DDX3Y Facilitates MYC-Driven Lymphomagenesis. Available at SSRN: https://ssrn.com/abstract=3520953 or http://dx.doi.org/10.2139/ssrn.3520953
This is a paper under consideration at Cell Press and has not been peer-reviewed.

Chun Gong

Wellcome Trust and MRC Cambridge Stem Cell Institute ( email )

Cambridge
United Kingdom

Joanna Krupka

Wellcome Trust and MRC Cambridge Stem Cell Institute ( email )

Cambridge
United Kingdom

Jie Gao

Wellcome Trust and MRC Cambridge Stem Cell Institute

Cambridge
United Kingdom

Nicholas Francis Grigoropoulos

Singapore General Hospital - Department of Haematology ( email )

Singapore

Michael Screen

The Babraham Institute ( email )

Babraham Hall House
Babraham Research Campus
Babraham, Cambridge, England CB22 3AT
United Kingdom

Zelvera Usheva

Wellcome Trust and MRC Cambridge Stem Cell Institute ( email )

Cambridge
United Kingdom

Francesco Cucco

University of Cambridge - Division of Cellular and Molecular Pathology ( email )

United Kingdom

Sharon Barrans

St. James’s Institute of Oncology - Haematological Malignancy Diagnostic Service

United Kingdom

Daniel Painter

University of York - Epidemiology and Cancer Statistics Group

York
United Kingdom

Mahirah Mohammed

Singapore General Hospital - Department of Haematology ( email )

Singapore

Björn Haupl

Goethe University Frankfurt - Department of Medicine II, Hematology/Oncology ( email )

Germany

Susanne Bornelöv

Wellcome Trust and MRC Cambridge Stem Cell Institute ( email )

Cambridge
United Kingdom

Igor Mozos

Francis Crick Institute ( email )

1 Midland Road
London, NW1 1AT
United Kingdom

Wei Meng

Nanyang Technological University (NTU) - School of Biological Sciences

Singapore

Peixun Zhou

Teesside University - School of Health & Life Sciences ( email )

United Kingdom

Alex Blain

Teesside University - School of Health & Life Sciences ( email )

United Kingdom

Sorcha Forde

University of Cambridge - Division of Cellular and Molecular Pathology ( email )

United Kingdom

Jamie Matthews

University of Cambridge - Division of Cellular and Molecular Pathology

United Kingdom

Michelle Guet Khim Tan

Singapore General Hospital - Department of Clinical Translational Research ( email )

Singapore

G.A. Amos Burke

Addenbrooke’s Hospital - Department of Paediatric Oncology ( email )

United Kingdom

Siu Kwan Sze

Nanyang Technological University (NTU) - School of Biological Sciences ( email )

Singapore

Philip Beer

Wellcome Trust Sanger Institute ( email )

Hinxton, Saffron Walden
Cambridge, England CB10 1SA
United Kingdom

Cathy Burton

St. James’s Institute of Oncology - Haematological Malignancy Diagnostic Service

United Kingdom

Peter J. Campbell

Wellcome Genome Campus - Cancer Genome Project

Hinxton, Saffron Walden
Cambridge, England CB10 1SA
United Kingdom

Wellcome Trust Sanger Institute

Hinxton, Saffron Walden
Cambridge, England CB10 1SA
United Kingdom

Vikki Rand

Teesside University - School of Health & Life Sciences ( email )

United Kingdom

Suzanne Turner

University of Cambridge - Division of Cellular and Molecular Pathology ( email )

United Kingdom

Jernej Ule

University of Cambridge - MRC Laboratory of Molecular Biology ( email )

Cambridge Biomedical Campus
Francis Crick Avenue
Cambridge, CB2 0QH
United Kingdom

Francis Crick Institute ( email )

1 Midland Road
London, NW1 1AT
United Kingdom

Eve Roman

University of York - Epidemiology and Cancer Statistics Group

York
United Kingdom

Reuben Tooze

St. James’s Institute of Oncology - Haematological Malignancy Diagnostic Service

United Kingdom

Thomas Oellerich

Goethe University Frankfurt - Department of Medicine II, Hematology/Oncology ( email )

Germany

Martin Turner

The Babraham Institute ( email )

Babraham Hall House
Babraham Research Campus
Babraham, Cambridge, England CB22 3AT
United Kingdom

Ming-Qing Du

University of Cambridge - Division of Cellular and Molecular Pathology ( email )

United Kingdom

Shamith Samarajiwa

University of Cambridge - MRC Cancer Unit ( email )

Hutchison/MRC Research Centre
Box 197, Cambridge Biomedical Campus
Cambridge, CB2 0XZ
United Kingdom

Daniel Hodson (Contact Author)

Wellcome Trust and MRC Cambridge Stem Cell Institute ( email )

Cambridge
United Kingdom

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