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 Matthews; Michelle 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

doi:10.1016/j.molcel.2021.07.041

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

Health Sciences

Research output: Contribution to journal › Article › peer-review

Abstract

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 language	English
Pages (from-to)	4059-4075
Number of pages	17
Journal	Molecular Cell
Volume	81
Issue number	19
DOIs	https://doi.org/10.1016/j.molcel.2021.07.041 https://doi.org/10.1016/j.molcel.2021.07.041
Publication status	Published - 7 Oct 2021

Bibliographical note

Keywords

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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©2021 The Author(s). Published by Elsevier Inc
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Cite this

Gong, C., Krupka, J. A., Gao, J., Grigoropoulos, N. F., Giotopoulos, G., Asby, R., Screen, M., Usheva, Z., Cucco, F., Barrans, S., Painter, D., Zaini, N. B. M., Haupl, B., Bornelöv, S., Ruiz De Los Mozos, I., Meng, W., Zhou, P., Blain, A. E., Forde, S., ... Hodson, D. J. (2021). Sequential inverse dysregulation of the RNA helicases DDX3X and DDX3Y facilitates MYC-driven lymphomagenesis. Molecular Cell, 81(19), 4059-4075. https://doi.org/10.1016/j.molcel.2021.07.041, https://doi.org/10.1016/j.molcel.2021.07.041

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title = "Sequential inverse dysregulation of the RNA helicases DDX3X and DDX3Y facilitates MYC-driven lymphomagenesis",

abstract = "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.",

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author = "Chun Gong and Krupka, {Joanna A} and Jie Gao and Grigoropoulos, {Nicholas F} and George Giotopoulos and Ryan Asby and Michael Screen and Zelvera Usheva and Francesco Cucco and Sharon Barrans and Daniel Painter and Zaini, {Nurmahirah Binte Mohammed} and Bj{\"o}rn Haupl and Susanne Bornel{\"o}v and {Ruiz De Los Mozos}, Igor and Wei Meng and Peixun Zhou and Blain, {Alex E} and Sorcha Forde and Jamie Matthews and {Khim Tan}, {Michelle Guet} and Burke, {G A Amos} and Sze, {Siu Kwan} and Philip Beer and Cathy Burton and Peter Campbell and Vikki Rand and Turner, {Suzanne D} and Jernej Ule and Eve Roman and Reuben Tooze and Thomas Oellerich and Huntly, {Brian J} and Martin Turner and Ming-Qing Du and Samarajiwa, {Shamith A} and Hodson, {Daniel J}",

year = "2021",

month = oct,

day = "7",

doi = "10.1016/j.molcel.2021.07.041",

language = "English",

volume = "81",

pages = "4059--4075",

journal = "Molecular Cell",

issn = "1097-2765",

publisher = "Cell Press",

number = "19",

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Gong, C, Krupka, JA, Gao, J, Grigoropoulos, NF, Giotopoulos, G, Asby, R, Screen, M, Usheva, Z, Cucco, F, Barrans, S, Painter, D, Zaini, NBM, Haupl, B, Bornelöv, S, Ruiz De Los Mozos, I, Meng, W, Zhou, P, Blain, AE, Forde, S, Matthews, J, Khim Tan, MG, Burke, GAA, Sze, SK, Beer, P, Burton, C, Campbell, P, Rand, V, Turner, SD, Ule, J, Roman, E, Tooze, R, Oellerich, T, Huntly, BJ, Turner, M, Du, M-Q, Samarajiwa, SA & Hodson, DJ 2021, 'Sequential inverse dysregulation of the RNA helicases DDX3X and DDX3Y facilitates MYC-driven lymphomagenesis', Molecular Cell, vol. 81, no. 19, pp. 4059-4075. https://doi.org/10.1016/j.molcel.2021.07.041, https://doi.org/10.1016/j.molcel.2021.07.041

TY - JOUR

T1 - Sequential inverse dysregulation of the RNA helicases DDX3X and DDX3Y facilitates MYC-driven lymphomagenesis

AU - Gong, Chun

AU - Krupka, Joanna A

AU - Gao, Jie

AU - Grigoropoulos, Nicholas F

AU - Giotopoulos, George

AU - Asby, Ryan

AU - Screen, Michael

AU - Usheva, Zelvera

AU - Cucco, Francesco

AU - Barrans, Sharon

AU - Painter, Daniel

AU - Zaini, Nurmahirah Binte Mohammed

AU - Haupl, Björn

AU - Bornelöv, Susanne

AU - Ruiz De Los Mozos, Igor

AU - Meng, Wei

AU - Zhou, Peixun

AU - Blain, Alex E

AU - Forde, Sorcha

AU - Matthews, Jamie

AU - Khim Tan, Michelle Guet

AU - Burke, G A Amos

AU - Sze, Siu Kwan

AU - Beer, Philip

AU - Burton, Cathy

AU - Campbell, Peter

AU - Rand, Vikki

AU - Turner, Suzanne D

AU - Ule, Jernej

AU - Roman, Eve

AU - Tooze, Reuben

AU - Oellerich, Thomas

AU - Huntly, Brian J

AU - Turner, Martin

AU - Du, Ming-Qing

AU - Samarajiwa, Shamith A

AU - Hodson, Daniel J

PY - 2021/10/7

Y1 - 2021/10/7

N2 - 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.

AB - 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.

KW - Adolescent

KW - Adult

KW - Aged

KW - Aged, 80 and over

KW - Animals

KW - B-Lymphocytes/enzymology

KW - Cell Line, Tumor

KW - Child

KW - Child, Preschool

KW - DEAD-box RNA Helicases/genetics

KW - Endoplasmic Reticulum Stress

KW - Female

KW - Gene Expression Regulation, Enzymologic

KW - Gene Expression Regulation, Neoplastic

KW - Humans

KW - Loss of Function Mutation

KW - Lymphoma, B-Cell/enzymology

KW - Male

KW - Mice, Transgenic

KW - Middle Aged

KW - Minor Histocompatibility Antigens/genetics

KW - Neoplasm Proteins/biosynthesis

KW - Protein Biosynthesis

KW - Proteome

KW - Proteostasis

KW - Proto-Oncogene Proteins c-myc/genetics

KW - Young Adult

U2 - 10.1016/j.molcel.2021.07.041

DO - 10.1016/j.molcel.2021.07.041

M3 - Article

C2 - 34437837

SN - 1097-2765

VL - 81

SP - 4059

EP - 4075

JO - Molecular Cell

JF - Molecular Cell

IS - 19

ER -