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dc.contributor.authorBueno, Claraen
dc.contributor.authorCalero-Nieto, Fernando Jen
dc.contributor.authorWang, Xiaonanen
dc.contributor.authorValdés-Mas, Rafaelen
dc.contributor.authorGutiérrez-Agüera, Franciscoen
dc.contributor.authorRoca-Ho, Heleiaen
dc.contributor.authorAyllon, Veronicaen
dc.contributor.authorReal, Pedro Jen
dc.contributor.authorArambilet, Daviden
dc.contributor.authorEspinosa, Lluisen
dc.contributor.authorTorres-Ruiz, Raulen
dc.contributor.authorAgraz-Doblas, Antonioen
dc.contributor.authorVarela, Ignacioen
dc.contributor.authorde Boer, Jasperen
dc.contributor.authorBigas, Annaen
dc.contributor.authorGottgens, Bertholden
dc.contributor.authorMarschalek, Rolfen
dc.contributor.authorMenendez, Pabloen
dc.date.accessioned2019-02-05T00:30:39Z
dc.date.available2019-02-05T00:30:39Z
dc.date.issued2019-06en
dc.identifier.issn0390-6078
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/288784
dc.description.abstractThe t(4;11)(q21;q23) translocation is associated with high-risk infant pro-B-cell acute lymphoblastic leukemia and arises prenatally during embryonic/fetal hematopoiesis. The developmental/pathogenic contribution of the t(4;11)-resulting MLL-AF4 (MA4) and AF4-MLL (A4M) fusions remains unclear; MA4 is always expressed in t(4;11)+ B-cell acute lymphoblastic leukemia patients, but the reciprocal fusion A4M is expressed in only half of the patients. Because prenatal leukemogenesis manifests as impaired early hematopoietic differentiation, we took advantage of well-established human embryonic stem cell-based hematopoietic differentiation models to study whether the A4M fusion cooperates with MA4 during early human hematopoietic development. Co-expression of A4M and MA4 strongly promoted the emergence of hematoendothelial precursors, both endothelial- and hemogenic-primed. Double fusion-expressing hematoendothelial precursors specified into significantly higher numbers of both hematopoietic and endothelial committed cells, irrespective of the differentiation protocol used and without hijacking survival/proliferation. Functional analysis of differentially expressed genes and differentially enriched H3K79me3 genomic regions by RNA-seq and H3K79me3 ChIP-seq, respectively, confirmed a hematopoietic/endothelial cell differentiation signature in double fusion-expressing hemato-endothelial precursors. Importantly, ChIP-seq analysis revealed a significant enrichment of H3K79 methylated regions specifically associated with HOX-A cluster genes in double fusion-expressing differentiating hematopoietic cells. Overall, these results establish a functional and molecular cooperation between MA4 and A4M fusions during human hematopoietic development.
dc.description.sponsorshipWellcome Trust, CRUK, Bloodwise, ERC, Generalitat de Catalunya, Spanish Ministry of Economy and Competitiveness, Spanish Association Against cancer, Health Institute Carlos III, NIHR GOSH BRC, Great Ormond Steet Hospital Children's Charity, Deutsche José Carreras Leukämie Stiftung, Obra Social La Caixa-Fundaciò Josep Carreras, Spanish Association of Cancer Research
dc.format.mediumPrint-Electronicen
dc.languageengen
dc.publisherFerrata Storti Foundation
dc.subjectHematopoietic Stem Cellsen
dc.subjectEndothelial Cellsen
dc.subjectAnimalsen
dc.subjectMice, Knockouten
dc.subjectHumansen
dc.subjectMiceen
dc.subjectOncogene Proteins, Fusionen
dc.subjectHistonesen
dc.subjectCoculture Techniquesen
dc.subjectCell Cycleen
dc.subjectApoptosisen
dc.subjectCell Differentiationen
dc.subjectHematopoiesisen
dc.subjectMethylationen
dc.subjectEmbryonic Developmenten
dc.subjectMyeloid-Lymphoid Leukemia Proteinen
dc.subjectHuman Embryonic Stem Cellsen
dc.titleEnhanced hemato-endothelial specification during human embryonic differentiation through developmental cooperation between AF4-MLL and MLL-AF4 fusions.en
dc.typeArticle
prism.endingPage1201
prism.issueIdentifier6en
prism.publicationDate2019en
prism.publicationNameHaematologicaen
prism.startingPage1189
prism.volume104en
dc.identifier.doi10.17863/CAM.36048
dcterms.dateAccepted2019-01-21en
rioxxterms.versionofrecord10.3324/haematol.2018.202044en
rioxxterms.versionAM
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserveden
rioxxterms.licenseref.startdate2019-06en
dc.contributor.orcidReal, Pedro J [0000-0001-7968-5353]
dc.contributor.orcidde Boer, Jasper [0000-0002-3220-8776]
dc.contributor.orcidGottgens, Berthold [0000-0001-6302-5705]
dc.contributor.orcidMenendez, Pablo [0000-0001-9372-1007]
dc.identifier.eissn1592-8721
rioxxterms.typeJournal Article/Reviewen
pubs.funder-project-idLeukaemia & Lymphoma Research (12029)
pubs.funder-project-idCancer Research UK (21762)
pubs.funder-project-idWellcome Trust (203151/Z/16/Z)
pubs.funder-project-idMEDICAL RESEARCH COUNCIL (MR/M008975/1)
pubs.funder-project-idMRC (MC_PC_12009)
pubs.funder-project-idMRC (MR/S036113/1)
rioxxterms.freetoread.startdate2020-01-24


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