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dc.contributor.authorPoggi, Marjorie
dc.contributor.authorCanault, Matthias
dc.contributor.authorFavier, Marie
dc.contributor.authorTurro, Ernest
dc.contributor.authorSaultier, Paul
dc.contributor.authorGhalloussi, Dorsaf
dc.contributor.authorBaccini, Veronique
dc.contributor.authorVidal, Lea
dc.contributor.authorMezzapesa, Anna
dc.contributor.authorChelghoum, Nadjim
dc.contributor.authorMohand-Oumoussa, Badreddine
dc.contributor.authorFalaise, Céline
dc.contributor.authorFavier, Rémi
dc.contributor.authorOuwehand, Willem H
dc.contributor.authorFiore, Mathieu
dc.contributor.authorPeiretti, Franck
dc.contributor.authorMorange, Pierre Emmanuel
dc.contributor.authorSaut, Noémie
dc.contributor.authorBernot, Denis
dc.contributor.authorGreinacher, Andreas
dc.contributor.authorBioResource, Nihr
dc.contributor.authorNurden, Alan T
dc.contributor.authorNurden, Paquita
dc.contributor.authorFreson, Kathleen
dc.contributor.authorTrégouët, David-Alexandre
dc.contributor.authorRaslova, Hana
dc.contributor.authorAlessi, Marie-Christine
dc.date.accessioned2018-05-31T14:15:42Z
dc.date.available2018-05-31T14:15:42Z
dc.date.issued2017-02
dc.identifier.issn0390-6078
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/276410
dc.description.abstractVariants in ETV6, which encodes a transcription repressor of the E26 transformation-specific family, have recently been reported to be responsible for inherited thrombocytopenia and hematologic malignancy. We sequenced the DNA from cases with unexplained dominant thrombocytopenia and identified six likely pathogenic variants in ETV6, of which five are novel. We observed low repressive activity of all tested ETV6 variants, and variants located in the E26 transformation-specific binding domain (encoding p.A377T, p.Y401N) led to reduced binding to corepressors. We also observed a large expansion of megakaryocyte colony-forming units derived from variant carriers and reduced proplatelet formation with abnormal cytoskeletal organization. The defect in proplatelet formation was also observed in control CD34+ cell-derived megakaryocytes transduced with lentiviral particles encoding mutant ETV6. Reduced expression levels of key regulators of the actin cytoskeleton CDC42 and RHOA were measured. Moreover, changes in the actin structures are typically accompanied by a rounder platelet shape with a highly heterogeneous size, decreased platelet arachidonic response, and spreading and retarded clot retraction in ETV6 deficient platelets. Elevated numbers of circulating CD34+ cells were found in p.P214L and p.Y401N carriers, and two patients from different families suffered from refractory anemia with excess blasts, while one patient from a third family was successfully treated for acute myeloid leukemia. Overall, our study provides novel insights into the role of ETV6 as a driver of cytoskeletal regulatory gene expression during platelet production, and the impact of variants resulting in platelets with altered size, shape and function and potentially also in changes in circulating progenitor levels.
dc.format.mediumPrint-Electronic
dc.languageeng
dc.publisherFerrata Storti Foundation (Haematologica)
dc.rightsAttribution-NonCommercial 4.0 International
dc.rights.urihttp://creativecommons.org/licenses/by-nc/4.0/
dc.subjectBlood Platelets
dc.subjectHematopoietic Stem Cells
dc.subjectMegakaryocytes
dc.subjectHumans
dc.subjectHyperplasia
dc.subjectRepressor Proteins
dc.subjectAntigens, CD34
dc.subjectBlood Cell Count
dc.subjectPlatelet Count
dc.subjectPedigree
dc.subjectFamily
dc.subjectCell Differentiation
dc.subjectThrombopoiesis
dc.subjectTranscription, Genetic
dc.subjectGene Expression Regulation
dc.subjectGenotype
dc.subjectPhenotype
dc.subjectGerm-Line Mutation
dc.subjectFemale
dc.subjectMale
dc.subjectProto-Oncogene Proteins c-ets
dc.titleGermline variants in ETV6 underlie reduced platelet formation, platelet dysfunction and increased levels of circulating CD34+ progenitors.
dc.typeArticle
prism.endingPage294
prism.issueIdentifier2
prism.publicationDate2017
prism.publicationNameHaematologica
prism.startingPage282
prism.volume102
dc.identifier.doi10.17863/CAM.23713
dcterms.dateAccepted2016-09-22
rioxxterms.versionofrecord10.3324/haematol.2016.147694
rioxxterms.versionVoR
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserved
rioxxterms.licenseref.startdate2017-02
dc.contributor.orcidTurro Bassols, Ernest [0000-0002-1820-6563]
dc.contributor.orcidOuwehand, Willem [0000-0002-7744-1790]
dc.identifier.eissn1592-8721
rioxxterms.typeJournal Article/Review
pubs.funder-project-idBritish Heart Foundation (None)
cam.issuedOnline2016-09-23
cam.orpheus.successThu Jan 30 12:59:11 GMT 2020 - The item has an open VoR version.
rioxxterms.freetoread.startdate2100-01-01


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Attribution-NonCommercial 4.0 International
Except where otherwise noted, this item's licence is described as Attribution-NonCommercial 4.0 International