PIM kinases as potential therapeutic targets in a subset of peripheral T cell lymphoma cases
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- dc.contributor.author Martín-Sánchez, Esperanzaca
- dc.contributor.author Real, Francisco X.ca
- dc.contributor.author Piris, Miguel A.ca
- dc.date.accessioned 2015-06-02T08:10:53Z
- dc.date.available 2015-06-02T08:10:53Z
- dc.date.issued 2014ca
- dc.description.abstract Currently, there is no efficient therapy for patients with peripheral T cell lymphoma (PTCL). The Proviral Integration site of Moloney murine leukemia virus (PIM) kinases are important mediators of cell survival. We aimed to determine the therapeutic value of PIM kinases because they are overexpressed in PTCL patients, T cell lines and primary tumoral T cells. PIM kinases were inhibited genetically (using small interfering and short hairpin RNAs) and pharmacologically (mainly with the pan-PIM inhibitor (PIMi) ETP-39010) in a panel of 8 PTCL cell lines. Effects on cell viability, apoptosis, cell cycle, key proteins and gene expression were evaluated. Individual inhibition of each of the PIM genes did not affect PTCL cell survival, partially because of a compensatory mechanism among the three PIM genes. In contrast, pharmacological inhibition of all PIM kinases strongly induced apoptosis in all PTCL cell lines, without cell cycle arrest, in part through the induction of DNA damage. Therefore, pan-PIMi synergized with Cisplatin. Importantly, pharmacological inhibition of PIM reduced primary tumoral T cell viability without affecting normal T cells ex vivo. Since anaplastic large cell lymphoma (ALK+ ALCL) cell lines were the most sensitive to the pan-PIMi, we tested the simultaneous inhibition of ALK and PIM kinases and found a strong synergistic effect in ALK+ ALCL cell lines. Our findings suggest that PIM kinase inhibition could be of therapeutic value in a subset of PTCL, especially when combined with ALK inhibitors, and might be clinically beneficial in ALK+ ALCL.en
- dc.description.sponsorship This work was supported by grants from the Asociación Española Contra el Cáncer, Fondo de Investigaciones Sanitarias (PI051623, PI052800 and FIS11/1759), RTICC (RD06/0020/0107) and Ministerio de Ciencia e Innovación (SAF2008-0387-1). EMS was supported by a grant from the Department of Education, Universities and Research of the Basque Government (BFI08.207). MSB was supported by a Contract Miguel Servet from Fondo de Investigaciones Sanitarias (CP11/00018).en
- dc.format.mimetype application/pdfca
- dc.identifier.citation Martín-Sánchez E, Odqvist L, Rodríguez-Pinilla SM, Sánchez-Beato M, Roncador G, Domínguez-González B et al. PIM kinases as potential therapeutic targets in a subset of peripheral T cell lymphoma cases. PLoS One. 2014; 9(11):e112148. DOI: 10.1371/journal.pone.0112148ca
- dc.identifier.doi http://dx.doi.org/10.1371/journal.pone.0112148
- dc.identifier.issn 1932-6203ca
- dc.identifier.uri http://hdl.handle.net/10230/23705
- dc.language.iso engca
- dc.publisher Public Library of Science (PLoS)ca
- dc.relation.ispartof PLoS One. 2014;9(11):e112148
- dc.relation.projectID info:eu-repo/grantAgreement/ES/3PN/SAF2008-0387
- dc.rights © 2014 Martín-Sánchez 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 creditedca
- dc.rights.accessRights info:eu-repo/semantics/openAccessca
- dc.subject.other Transducció de senyal cel·lularca
- dc.subject.other Cèl·lules -- Interaccióca
- dc.title PIM kinases as potential therapeutic targets in a subset of peripheral T cell lymphoma casesen
- dc.type info:eu-repo/semantics/articleca
- dc.type.version info:eu-repo/semantics/publishedVersionca