PIM kinases as potential therapeutic targets in a subset of peripheral T cell lymphoma cases

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 overexpress...

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Authors: Martín-Sánchez, Esperanza, Real, Francisco X., Piris, Miguel A.
Format: article
Status:Published version
Publication Date:2014
Country:España
Institution:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
Repository:Recercat. Dipósit de la Recerca de Catalunya
OAI Identifier:oai:recercat.cat:10230/23705
Online Access:http://hdl.handle.net/10230/23705
http://dx.doi.org/10.1371/journal.pone.0112148
Access Level:Open access
Keyword:Transducció de senyal cel·lular
Cèl·lules -- Interacció
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spelling PIM kinases as potential therapeutic targets in a subset of peripheral T cell lymphoma casesMartín-Sánchez, EsperanzaReal, Francisco X.Piris, Miguel A.Transducció de senyal cel·lularCèl·lules -- InteraccióCurrently, 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.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).Public Library of Science (PLoS)201520152014info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdfapplication/pdfhttp://hdl.handle.net/10230/23705http://dx.doi.org/10.1371/journal.pone.0112148reponame:Recercat. Dipósit de la Recerca de Catalunyainstname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)InglésPLoS One. 2014;9(11):e112148info:eu-repo/grantAgreement/ES/3PN/SAF2008-0387© 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 creditedinfo:eu-repo/semantics/openAccessoai:recercat.cat:10230/237052026-05-29T05:05:01Z
dc.title.none.fl_str_mv PIM kinases as potential therapeutic targets in a subset of peripheral T cell lymphoma cases
title PIM kinases as potential therapeutic targets in a subset of peripheral T cell lymphoma cases
spellingShingle PIM kinases as potential therapeutic targets in a subset of peripheral T cell lymphoma cases
Martín-Sánchez, Esperanza
Transducció de senyal cel·lular
Cèl·lules -- Interacció
title_short PIM kinases as potential therapeutic targets in a subset of peripheral T cell lymphoma cases
title_full PIM kinases as potential therapeutic targets in a subset of peripheral T cell lymphoma cases
title_fullStr PIM kinases as potential therapeutic targets in a subset of peripheral T cell lymphoma cases
title_full_unstemmed PIM kinases as potential therapeutic targets in a subset of peripheral T cell lymphoma cases
title_sort PIM kinases as potential therapeutic targets in a subset of peripheral T cell lymphoma cases
dc.creator.none.fl_str_mv Martín-Sánchez, Esperanza
Real, Francisco X.
Piris, Miguel A.
author Martín-Sánchez, Esperanza
author_facet Martín-Sánchez, Esperanza
Real, Francisco X.
Piris, Miguel A.
author_role author
author2 Real, Francisco X.
Piris, Miguel A.
author2_role author
author
dc.subject.none.fl_str_mv Transducció de senyal cel·lular
Cèl·lules -- Interacció
topic Transducció de senyal cel·lular
Cèl·lules -- Interacció
description 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.
publishDate 2014
dc.date.none.fl_str_mv 2014
2015
2015
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10230/23705
http://dx.doi.org/10.1371/journal.pone.0112148
url http://hdl.handle.net/10230/23705
http://dx.doi.org/10.1371/journal.pone.0112148
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv PLoS One. 2014;9(11):e112148
info:eu-repo/grantAgreement/ES/3PN/SAF2008-0387
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv Public Library of Science (PLoS)
publisher.none.fl_str_mv Public Library of Science (PLoS)
dc.source.none.fl_str_mv reponame:Recercat. Dipósit de la Recerca de Catalunya
instname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
instname_str Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
reponame_str Recercat. Dipósit de la Recerca de Catalunya
collection Recercat. Dipósit de la Recerca de Catalunya
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,81155

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