Repository logo
 

Promoter-bound METTL3 maintains myeloid leukaemia by m6A-dependent translation control.

Simple item page
cam.issuedOnline2017-11-27
dc.contributor.authorBarbieri, Isaia
dc.contributor.authorTzelepis, Konstantinos
dc.contributor.authorPandolfini, Luca
dc.contributor.authorShi, Junwei
dc.contributor.authorMillán-Zambrano, Gonzalo
dc.contributor.authorRobson, Samuel C
dc.contributor.authorAspris, Demetrios
dc.contributor.authorMigliori, Valentina
dc.contributor.authorBannister, Andrew J
dc.contributor.authorHan, Namshik
dc.contributor.authorDe Braekeleer, Etienne
dc.contributor.authorPonstingl, Hannes
dc.contributor.authorHendrick, Alan
dc.contributor.authorVakoc, Christopher R
dc.contributor.authorVassiliou, George S
dc.contributor.authorKouzarides, Tony
dc.contributor.orcidBarbieri, Isaia [0000-0003-3035-8970]
dc.contributor.orcidTzelepis, Konstantinos [0000-0002-4865-7648]
dc.contributor.orcidPandolfini, Luca [0000-0003-1444-8167]
dc.contributor.orcidBannister, Andrew [0000-0002-6312-4436]
dc.contributor.orcidHan, Namshik [0000-0002-7741-6384]
dc.contributor.orcidHendrick, Alan [0000-0002-8604-0462]
dc.contributor.orcidVassiliou, George [0000-0003-4337-8022]
dc.contributor.orcidKouzarides, Tony [0000-0002-8918-4162]
dc.date.accessioned2018-02-05T09:13:02Z
dc.date.available2018-02-05T09:13:02Z
dc.date.issued2017-12-07
dc.description.abstractN6-methyladenosine (m6A) is an abundant internal RNA modification in both coding and non-coding RNAs that is catalysed by the METTL3-METTL14 methyltransferase complex. However, the specific role of these enzymes in cancer is still largely unknown. Here we define a pathway that is specific for METTL3 and is implicated in the maintenance of a leukaemic state. We identify METTL3 as an essential gene for growth of acute myeloid leukaemia cells in two distinct genetic screens. Downregulation of METTL3 results in cell cycle arrest, differentiation of leukaemic cells and failure to establish leukaemia in immunodeficient mice. We show that METTL3, independently of METTL14, associates with chromatin and localizes to the transcriptional start sites of active genes. The vast majority of these genes have the CAATT-box binding protein CEBPZ present at the transcriptional start site, and this is required for recruitment of METTL3 to chromatin. Promoter-bound METTL3 induces m6A modification within the coding region of the associated mRNA transcript, and enhances its translation by relieving ribosome stalling. We show that genes regulated by METTL3 in this way are necessary for acute myeloid leukaemia. Together, these data define METTL3 as a regulator of a chromatin-based pathway that is necessary for maintenance of the leukaemic state and identify this enzyme as a potential therapeutic target for acute myeloid leukaemia.
dc.format.mediumPrint-Electronic
dc.identifier.doi10.17863/CAM.18619
dc.identifier.eissn1476-4687
dc.identifier.issn0028-0836
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/271626
dc.languageeng
dc.language.isoeng
dc.publisherSpringer Science and Business Media LLC
dc.publisher.urlhttp://dx.doi.org/10.1038/nature24678
dc.subjectAdenosine
dc.subjectAnimals
dc.subjectCRISPR-Cas Systems
dc.subjectCell Line, Tumor
dc.subjectCell Proliferation
dc.subjectChromatin
dc.subjectFemale
dc.subjectGene Expression Regulation, Neoplastic
dc.subjectGenes, Neoplasm
dc.subjectHumans
dc.subjectLeukemia, Myeloid, Acute
dc.subjectMethyltransferases
dc.subjectMice
dc.subjectPromoter Regions, Genetic
dc.subjectProtein Biosynthesis
dc.subjectRNA, Messenger
dc.subjectRibosomes
dc.subjectTranscription Initiation Site
dc.titlePromoter-bound METTL3 maintains myeloid leukaemia by m6A-dependent translation control.
dc.typeArticle
dcterms.dateAccepted2017-10-25
prism.endingPage131
prism.issueIdentifier7683
prism.publicationDate2017
prism.publicationNameNature
prism.startingPage126
prism.volume552
pubs.funder-project-idEuropean Research Council (268569)
pubs.funder-project-idKay Kendall Leukaemia Fund (KKL1103)
pubs.funder-project-idMedical Research Council (MC_PC_12009)
pubs.funder-project-idCancer Research UK (17001)
pubs.funder-project-idWellcome Trust (092096/Z/10/Z)
pubs.funder-project-idCancer Research UK (23015)
pubs.funder-project-idCancer Research Uk (None)
pubs.funder-project-idWellcome Trust (095663/Z/11/A)
rioxxterms.licenseref.startdate2017-12
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserved
rioxxterms.typeJournal Article/Review
rioxxterms.versionAM
rioxxterms.versionofrecord10.1038/nature24678

Files

Original bundle
Now showing 1 - 1 of 1
Thumbnail Image
Name:
PDFsam_merge.pdf
Size:
10 MB
Format:
Adobe Portable Document Format
Description:
Accepted version
Licence
http://www.rioxx.net/licenses/all-rights-reserved
Download
License bundle
Now showing 1 - 1 of 1
No Thumbnail Available
Name:
DepositLicenceAgreement.pdf
Size:
417.78 KB
Format:
Adobe Portable Document Format
Download

Collections

Scholarly Works - Wellcome Trust/Cancer Research UK Gurdon Institute