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The bone marrow-mediated protection of myeloproliferative neoplastic cells to Vorinostat and Ruxolitinib relies on the activation of JNK and PI3K signalling pathways

2015-12-01Artigo científico Acesso aberto
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dc.contributor.authorCardoso, Bruno A
dc.contributor.authorBelo, Hélio
dc.contributor.authorBarata, João T
dc.contributor.authorAlmeida, António M
dc.contributor.institutionNOVA Medical School|Faculdade de Ciências Médicas (NMS|FCM)
dc.contributor.institutionCentro de Estudos de Doenças Crónicas (CEDOC)
dc.contributor.pblPLOS - Public Library of Science
dc.date.accessioned2017-06-08T22:01:30Z
dc.date.available2017-06-08T22:01:30Z
dc.date.issued2015-12-01
dc.descriptionThis study was funded by research grants from "Instituto Portugues de Oncologia de Lisboa-Francisco Gentil" (IPOL-FG), "Associacao Portuguesa Contra a Leucemia" (APCL) and "Liga Portuguesa Contra o Cancro" (LPCC). BAC is a recipient of a Post-Doc fellowship from "Fundacao para a Ciencia e Tecnologia" (FCT-SFRH/BPD/79209/2011) and HB from LPCC. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
dc.description.abstractThe classical BCR-ABL-negative Myeloproliferative Neoplasms (MPN) are a group of heterogeneous haematological diseases characterized by constitutive JAK-STAT pathway activation. Targeted therapy with Ruxolitinib, a JAK1/2-specific inhibitor, achieves symptomatic improvement but does not eliminate the neoplastic clone. Similar effects are seen with histone deacetylase inhibitors (HDACi), albeit with poorer tolerance. Here, we show that bone marrow (BM) stromal cells (HS-5) protected MPN-derived cell lines (SET-2; HEL and UKE-1) and MPN patient-derived BM cells from the cytotoxic effects of Ruxolitinib and the HDACi Vorinostat. This protective effect was mediated, at least in part, by the secretion of soluble factors from the BM stroma. In addition, it correlated with the activation of signalling pathways important for cellular homeostasis, such as JAK-STAT, PI3K, JNK, MEK-ERK and NF-kappa B. Importantly, the pharmacological inhibition of JNK and PI3K pathways completely abrogated the BM protective effect on MPN cell lines and MPN patient samples. Our findings shed light on mechanisms of tumour survival and may indicate novel therapeutic approaches for the treatment of MPN.en
dc.description.versionpublishersversion
dc.description.versionpublished
dc.format.extent3035484
dc.identifier.doi10.1371/journal.pone.0143897
dc.identifier.issn1932-6203
dc.identifier.otherPURE: 514120
dc.identifier.otherPURE UUID: ea455e2f-7762-433b-8bda-a42f04f63fac
dc.identifier.otherresearchoutputwizard: 51872
dc.identifier.otherPubMed: 26623653
dc.identifier.otherWOS: 000365891600072
dc.identifier.otherScopus: 84957108370
dc.identifier.urihttp://hdl.handle.net/10362/21495
dc.language.isoeng
dc.peerreviewedyes
dc.relationinfo:eu-repo/grantAgreement/FCT/SFRH/SFRH%2FBPD%2F79209%2F2011/PT
dc.subjectHISTONE-DEACETYLASE INHIBITOR
dc.subjectPOLYCYTHEMIA-VERA
dc.subjectPRIMARY MYELOFIBROSIS
dc.subjectMUTATION
dc.subjectESSENTIAL THROMBOCYTHEMIA
dc.subjectACUTE LYMPHOBLASTIC-LEUKEMIA
dc.subjectTYROSINE KINASE JAK2
dc.subjectSTEM-CELL
dc.subjectPHASE-II
dc.subjectPROGENITOR CELLS
dc.subjectMultidisciplinary Sciences
dc.titleThe bone marrow-mediated protection of myeloproliferative neoplastic cells to Vorinostat and Ruxolitinib relies on the activation of JNK and PI3K signalling pathwaysen
dc.typejournal article
degois.publication.firstPage
degois.publication.issue12
degois.publication.lastPage
degois.publication.titlePLoS ONE
degois.publication.volume10
dspace.entity.typePublication
oaire.awardNumberSFRH/BPD/79209/2011
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/SFRH/SFRH%2FBPD%2F79209%2F2011/PT
oaire.fundingStreamSFRH
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.nameFundação para a Ciência e a Tecnologia
rcaap.rightsopenAccess
relation.isProjectOfPublication9b6f44c5-945a-44c3-85f4-ccf14e2240c6
relation.isProjectOfPublication.latestForDiscovery9b6f44c5-945a-44c3-85f4-ccf14e2240c6

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