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^*

^*Corresponding author for this work

Cancer and Genomic Sciences

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

24 Downloads (Pure)

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 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.e11
Number of pages	28
Journal	Molecular Cell
Volume	81
Issue number	19
Early online date	25 Aug 2021
DOIs	https://doi.org/10.1016/j.molcel.2021.07.041
Publication status	Published - 7 Oct 2021

Bibliographical note

Funding Information:
D.J.H. was supported by fellowships from the MRC (MR/M008584/1) and Cancer Research UK (CRUK) (RCCFEL∖100072). C.G. was supported by a fellowship from the Kay Kendall Leukaemia Fund (KKLF1398). J.A.K. was supported by a CRUK studentship (C9685/A25163). The Hodson laboratory is supported by Blood Cancer UK (grant ID 15022), the Kay Kendall Leukaemia Fund (KKL1144), the Evelyn Trust (ET19/27), and the Addenbrooke's Charitable Trust (900186). Research in the Hodson and Huntly laboratories was funded in part by the Wellcome Trust, which supported the Wellcome – MRC Cambridge Stem Cell Institute (203151/Z/16/Z) (for the purpose of Open Access, the author has applied a CC BY public copyright license to any author-accepted manuscript version arising from this submission), the CRUK Cambridge Major Centre (C49940/A25117), and the NIHR Cambridge Biomedical Research Centre (BRC-1215-20014) (the views expressed here are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care). B.J.H. was supported by CRUK (C18680/A25508) and the European Research Council (647685). Targeted lymphoma sequencing was funded by a grant from Blood Cancer UK to E.R. N.F.G. was funded by the Singapore National Medical Research Council (NMRC/TA/0051/2016). S.F. J.M. and S.D.T. were supported by the Alex Hume Foundation. J.U. was supported by the European Research Council under the European Union's Seventh Framework Programme (617837-Translate). The Francis Crick Institute receives its core funding from CRUK (FC001110), the UK Medical Research Council (FC001110), and the Wellcome Trust (FC001110). V.R. was supported by a Blood Cancer UK Senior Bennett Fellowship (12005) and the North East Promenaders Against Cancer (NEPAC), the JGW Patterson Foundation, and the Little Princess Trust. The Turner lab is supported by the BBSRC (BBS/E/B/000C0428) and a Wellcome Investigator award (200823/Z/16/Z). S.S. received core funding from the MRC (MC_UU_12022/10). We thank the patients, clinicians, and staff who participated in the collection of material and clinical data at the Children's Cancer and Leukaemia Group (CCLG) Tissue Bank. We are grateful to Joanna Baxter and Kay Elston from the Cambridge Blood and Stem Cell Bank and Alice Mitchell and Jessica Bewick from the ENT Department, Cambridge University Hospitals, for the supply of tonsil tissue. We thank Claudia Ribeiro de Almeida, George Vassiliou, and Graham Packham for critical reading of the manuscript. Graphical abstract was generated with BioRender.com.

Publisher Copyright:
© 2021 The Author(s)

Keywords

Burkitt lymphoma
DDX3X
germinal center
MYC
proteotoxic stress
RNA helicase
translation

ASJC Scopus subject areas

Molecular Biology
Cell Biology

Access to Document

10.1016/j.molcel.2021.07.041Licence: Creative Commons: Attribution (CC BY)

GongC2021SequentialFinal published version, 5.5 MBLicence: Creative Commons: Attribution (CC BY)

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.e11. https://doi.org/10.1016/j.molcel.2021.07.041

@article{e7207f993d744233ada72f1e5b93ae71,

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

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 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.",

keywords = "Burkitt lymphoma, DDX3X, germinal center, MYC, proteotoxic stress, RNA helicase, translation",

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 Du, {Ming Qing} and Samarajiwa, {Shamith A.} and Hodson, {Daniel J.}",

note = "Funding Information: D.J.H. was supported by fellowships from the MRC (MR/M008584/1) and Cancer Research UK (CRUK) (RCCFEL∖100072). C.G. was supported by a fellowship from the Kay Kendall Leukaemia Fund (KKLF1398). J.A.K. was supported by a CRUK studentship (C9685/A25163). The Hodson laboratory is supported by Blood Cancer UK (grant ID 15022), the Kay Kendall Leukaemia Fund (KKL1144), the Evelyn Trust (ET19/27), and the Addenbrooke's Charitable Trust (900186). Research in the Hodson and Huntly laboratories was funded in part by the Wellcome Trust, which supported the Wellcome – MRC Cambridge Stem Cell Institute (203151/Z/16/Z) (for the purpose of Open Access, the author has applied a CC BY public copyright license to any author-accepted manuscript version arising from this submission), the CRUK Cambridge Major Centre (C49940/A25117), and the NIHR Cambridge Biomedical Research Centre (BRC-1215-20014) (the views expressed here are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care). B.J.H. was supported by CRUK (C18680/A25508) and the European Research Council (647685). Targeted lymphoma sequencing was funded by a grant from Blood Cancer UK to E.R. N.F.G. was funded by the Singapore National Medical Research Council (NMRC/TA/0051/2016). S.F. J.M. and S.D.T. were supported by the Alex Hume Foundation. J.U. was supported by the European Research Council under the European Union's Seventh Framework Programme (617837-Translate). The Francis Crick Institute receives its core funding from CRUK (FC001110), the UK Medical Research Council (FC001110), and the Wellcome Trust (FC001110). V.R. was supported by a Blood Cancer UK Senior Bennett Fellowship (12005) and the North East Promenaders Against Cancer (NEPAC), the JGW Patterson Foundation, and the Little Princess Trust. The Turner lab is supported by the BBSRC (BBS/E/B/000C0428) and a Wellcome Investigator award (200823/Z/16/Z). S.S. received core funding from the MRC (MC_UU_12022/10). We thank the patients, clinicians, and staff who participated in the collection of material and clinical data at the Children's Cancer and Leukaemia Group (CCLG) Tissue Bank. We are grateful to Joanna Baxter and Kay Elston from the Cambridge Blood and Stem Cell Bank and Alice Mitchell and Jessica Bewick from the ENT Department, Cambridge University Hospitals, for the supply of tonsil tissue. We thank Claudia Ribeiro de Almeida, George Vassiliou, and Graham Packham for critical reading of the manuscript. Graphical abstract was generated with BioRender.com. Publisher Copyright: {\textcopyright} 2021 The Author(s) ",

year = "2021",

month = oct,

day = "7",

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

language = "English",

volume = "81",

pages = "4059--4075.e11",

journal = "Molecular Cell",

issn = "1097-2765",

publisher = "Elsevier",

number = "19",

}

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, MQ, 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.e11. 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.

N1 - Funding Information: D.J.H. was supported by fellowships from the MRC (MR/M008584/1) and Cancer Research UK (CRUK) (RCCFEL∖100072). C.G. was supported by a fellowship from the Kay Kendall Leukaemia Fund (KKLF1398). J.A.K. was supported by a CRUK studentship (C9685/A25163). The Hodson laboratory is supported by Blood Cancer UK (grant ID 15022), the Kay Kendall Leukaemia Fund (KKL1144), the Evelyn Trust (ET19/27), and the Addenbrooke's Charitable Trust (900186). Research in the Hodson and Huntly laboratories was funded in part by the Wellcome Trust, which supported the Wellcome – MRC Cambridge Stem Cell Institute (203151/Z/16/Z) (for the purpose of Open Access, the author has applied a CC BY public copyright license to any author-accepted manuscript version arising from this submission), the CRUK Cambridge Major Centre (C49940/A25117), and the NIHR Cambridge Biomedical Research Centre (BRC-1215-20014) (the views expressed here are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care). B.J.H. was supported by CRUK (C18680/A25508) and the European Research Council (647685). Targeted lymphoma sequencing was funded by a grant from Blood Cancer UK to E.R. N.F.G. was funded by the Singapore National Medical Research Council (NMRC/TA/0051/2016). S.F. J.M. and S.D.T. were supported by the Alex Hume Foundation. J.U. was supported by the European Research Council under the European Union's Seventh Framework Programme (617837-Translate). The Francis Crick Institute receives its core funding from CRUK (FC001110), the UK Medical Research Council (FC001110), and the Wellcome Trust (FC001110). V.R. was supported by a Blood Cancer UK Senior Bennett Fellowship (12005) and the North East Promenaders Against Cancer (NEPAC), the JGW Patterson Foundation, and the Little Princess Trust. The Turner lab is supported by the BBSRC (BBS/E/B/000C0428) and a Wellcome Investigator award (200823/Z/16/Z). S.S. received core funding from the MRC (MC_UU_12022/10). We thank the patients, clinicians, and staff who participated in the collection of material and clinical data at the Children's Cancer and Leukaemia Group (CCLG) Tissue Bank. We are grateful to Joanna Baxter and Kay Elston from the Cambridge Blood and Stem Cell Bank and Alice Mitchell and Jessica Bewick from the ENT Department, Cambridge University Hospitals, for the supply of tonsil tissue. We thank Claudia Ribeiro de Almeida, George Vassiliou, and Graham Packham for critical reading of the manuscript. Graphical abstract was generated with BioRender.com. Publisher Copyright: © 2021 The Author(s)

PY - 2021/10/7

Y1 - 2021/10/7

N2 - 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 - 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 - Burkitt lymphoma

KW - DDX3X

KW - germinal center

KW - MYC

KW - proteotoxic stress

KW - RNA helicase

KW - translation

UR - http://www.scopus.com/inward/record.url?scp=85116573195&partnerID=8YFLogxK

U2 - 10.1016/j.molcel.2021.07.041

DO - 10.1016/j.molcel.2021.07.041

M3 - Article

C2 - 34437837

AN - SCOPUS:85116573195

SN - 1097-2765

VL - 81

SP - 4059-4075.e11

JO - Molecular Cell

JF - Molecular Cell

IS - 19

ER -

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

Abstract

Bibliographical note

Keywords

ASJC Scopus subject areas

Access to Document

Fingerprint

Cite this