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dc.contributor.authorGhezzo, MN
dc.contributor.authorFernandes, MT
dc.contributor.authorPacheco-Leyva, I
dc.contributor.authorRodrigues, PM
dc.contributor.authorMachado, RS
dc.contributor.authorAraujo, MAS
dc.contributor.authorKalathur, RK
dc.contributor.authorFutschik, Matthias
dc.contributor.authorAlves, N
dc.contributor.authordos Santos, NR
dc.date.accessioned2018-09-27T06:03:21Z
dc.date.issued2018-12
dc.identifier.issn0143-3334
dc.identifier.issn1460-2180
dc.identifier.urihttp://hdl.handle.net/10026.1/12424
dc.description.abstract

T-cell acute lymphoblastic leukemia (T-ALL) and T-lymphoblastic lymphomas (T-LBL) are aggressive malignancies of thymocytes. The role of thymic microenvironmental cells and stromal factors in thymocyte malignant transformation and T-ALL development remains little explored. Here, using the TEL-JAK2 transgenic (TJ2-Tg) mouse model of T-ALL/LBL, which is driven by constitutive JAK/STAT signaling and characterized by the acquisition of Notch1 mutations, we sought to identify stromal cell alterations associated with thymic leukemogenesis. Immunofluorescence analyses showed that thymic lymphomas presented epithelial areas characterized by keratin (Krt) 5 and Krt8 expression, adjacently to epithelial-free areas negative for Krt expression. Both areas contained abundant laminin (extracellular matrix) and ER-TR7+ (fibroblasts) CD31+ (endothelial) and CD11c+ (dendritic) cells. Besides Krt5, Krt-positive areas harbored medullary thymic epithelial cells (TECs) labeled by Ulex europaeus agglutinin-1. By performing flow cytometry and RNA sequencing analyses of thymic lymphomas, we observed an enrichment in medullary TEC markers in detriment of cortical TEC markers. To assess whether TECs are important for T-ALL/LBL development, we generated TJ2-Tg mice heterozygous for the FoxN1 transcription factor nude null mutation (Foxn1+/nu). Strikingly, in TJ2-Tg;Foxn1+/nu compound mice, both emergence of malignant cells in preleukemic thymi and overt T-ALL onset were significantly delayed. Moreover, in transplantation assays, leukemic cell expansion within the thymus of recipient Foxn1+/nu mice was reduced as compared with control littermates. Since thymopoesis is largely normal in Foxn1+/nu mice, these results indicate that FoxN1 haploinsufficiency in TECs has a more profound impact in thymic leukemogenesis.

dc.format.extent1463-1476
dc.format.mediumPrint
dc.languageen
dc.language.isoen
dc.publisherOxford University Press (OUP)
dc.rightsAttribution-NonCommercial-NoDerivatives 4.0 International
dc.rightsAttribution-NonCommercial-NoDerivatives 4.0 International
dc.rightsAttribution-NonCommercial-NoDerivatives 4.0 International
dc.rightsAttribution-NonCommercial-NoDerivatives 4.0 International
dc.rightsAttribution-NonCommercial-NoDerivatives 4.0 International
dc.rightsAttribution-NonCommercial-NoDerivatives 4.0 International
dc.rightsAttribution-NonCommercial-NoDerivatives 4.0 International
dc.rightsAttribution-NonCommercial-NoDerivatives 4.0 International
dc.rightsAttribution-NonCommercial-NoDerivatives 4.0 International
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/
dc.subjectAnimals
dc.subjectBiomarkers, Tumor
dc.subjectCarcinogenesis
dc.subjectCell Differentiation
dc.subjectDisease Models, Animal
dc.subjectEpithelial Cells
dc.subjectEpithelium
dc.subjectForkhead Transcription Factors
dc.subjectLeukemia, T-Cell
dc.subjectMice
dc.subjectMice, Inbred C57BL
dc.subjectMice, Nude
dc.subjectMice, Transgenic
dc.subjectMutation
dc.subjectSequence Analysis, RNA
dc.subjectSignal Transduction
dc.subjectStromal Cells
dc.subjectThymus Gland
dc.titleFoxN1-dependent thymic epithelial cells promote T-cell leukemia development
dc.typejournal-article
dc.typeJournal Article
dc.typeResearch Support, Non-U.S. Gov't
plymouth.author-urlhttps://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000456035400006&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=11bb513d99f797142bcfeffcc58ea008
plymouth.issue12
plymouth.volume39
plymouth.publication-statusPublished
plymouth.journalCarcinogenesis
dc.identifier.doi10.1093/carcin/bgy127
plymouth.organisational-group/Plymouth
plymouth.organisational-group/Plymouth/Faculty of Health
plymouth.organisational-group/Plymouth/Users by role
dc.publisher.placeEngland
dcterms.dateAccepted2018-08-29
dc.rights.embargodate2019-9-26
dc.identifier.eissn1460-2180
dc.rights.embargoperiodNot known
rioxxterms.versionAccepted Manuscript
rioxxterms.versionofrecord10.1093/carcin/bgy127
rioxxterms.licenseref.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/
rioxxterms.licenseref.startdate2018-12
rioxxterms.typeJournal Article/Review


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