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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

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dc.contributor.authorCardoso, Bruno A.
dc.contributor.authorBelo, Hélio
dc.contributor.authorBarata, João T.
dc.contributor.authorAlmeida, António M.
dc.date.accessioned2022-02-11T16:07:06Z
dc.date.available2022-02-11T16:07:06Z
dc.date.issued2015
dc.descriptionCopyright: © 2015 Cardoso et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are creditedpt_PT
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-κB. 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.pt_PT
dc.description.sponsorshipThis study was funded by research grants from "Instituto Português de Oncologia de Lisboa—Francisco Gentil" (IPOL-FG), "Associação Portuguesa Contra a Leucemia" (APCL) and "Liga Portuguesa Contra o Cancro" (LPCC). BAC is a recipient of a Post-Doc fellowship from "Fundação para a Ciência e Tecnologia" (FCT—SFRH/BPD/79209/2011) and HB from LPCC.pt_PT
dc.description.versioninfo:eu-repo/semantics/publishedVersionpt_PT
dc.identifier.citationPLoS One. 2015 Dec 1;10(12):e0143897pt_PT
dc.identifier.doi10.1371/journal.pone.0143897pt_PT
dc.identifier.eissn1932-6203
dc.identifier.urihttp://hdl.handle.net/10451/51233
dc.language.isoengpt_PT
dc.peerreviewedyespt_PT
dc.publisherPLOSpt_PT
dc.relation.publisherversionhttps://journals.plos.org/plosone/pt_PT
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/pt_PT
dc.titleThe bone marrow-mediated protection of myeloproliferative neoplastic cells to Vorinostat and Ruxolitinib relies on the activation of JNK and PI3K signalling pathwayspt_PT
dc.typejournal article
dspace.entity.typePublication
oaire.awardNumberSFRH/BPD/79209/2011
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/SFRH/SFRH%2FBPD%2F79209%2F2011/PT
oaire.citation.issue12pt_PT
oaire.citation.titlePLOS ONEpt_PT
oaire.citation.volume10pt_PT
oaire.fundingStreamSFRH
person.familyNameBarata
person.givenNameJoão
person.identifier.orcid0000-0002-4826-8976
person.identifier.ridD-9181-2015
person.identifier.scopus-author-id7006937224
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.nameFundação para a Ciência e a Tecnologia
rcaap.rightsopenAccesspt_PT
rcaap.typearticlept_PT
relation.isAuthorOfPublication06f27f7f-1c6c-4c03-a70d-52f8a388bd3b
relation.isAuthorOfPublication.latestForDiscovery06f27f7f-1c6c-4c03-a70d-52f8a388bd3b
relation.isProjectOfPublication150f4828-37de-45c5-a23b-26234017b501
relation.isProjectOfPublication.latestForDiscovery150f4828-37de-45c5-a23b-26234017b501

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