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Identification of tipifarnib sensitivity biomarkers in T-cell acute lymphoblastic leukemia and T-cell lymphoma

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dc.contributor.author Alonso Alonso, Ruth
dc.contributor.author Mondéjar, Rufino
dc.contributor.author Martínez, Nerea
dc.contributor.author García Diaz, Nuria
dc.contributor.author Pérez, Cristina
dc.contributor.author Merino, David
dc.contributor.author Rodríguez, Marta
dc.contributor.author Esteve-Codina, Anna
dc.contributor.author Fusté, Berta
dc.contributor.author Gut, Marta
dc.contributor.author Burrows, Francis
dc.contributor.author Scholz, Catherine
dc.contributor.author Vaqué, José Pedro
dc.contributor.author Gualberto, Antonio
dc.contributor.author Piris, Miguel A.
dc.date.accessioned 2020-05-14T06:48:58Z
dc.date.available 2020-05-14T06:48:58Z
dc.date.issued 2020
dc.identifier.citation Alonso-Alonso R, Mondéjar R, Martínez N, García-Diaz N, Pérez C, Merino D, Rodríguez M, Esteve-Codina A, Fuste B, Gut M, Burrows F, Scholz C, Vaqué JP, Gualberto A, Piris MÁ. Identification of tipifarnib sensitivity biomarkers in T-cell acute lymphoblastic leukemia and T-cell lymphoma. Sci Rep. 2020; 10(1):6721. DOI: 10.1038/s41598-020-63434-5
dc.identifier.issn 2045-2322
dc.identifier.uri http://hdl.handle.net/10230/44537
dc.description.abstract Patients diagnosed with T-cell leukemias and T-cell lymphomas (TCLs) still have a poor prognosis and an inadequate response to current therapies, highlighting the need for targeted treatments. We have analyzed the potential therapeutic value of the farnesyltransferase inhibitor, tipifarnib, in 25 TCL cell lines through the identification of genomic and/or immunohistochemical markers of tipifarnib sensitivity. More than half of the cell lines (60%) were considered to be sensitive. Tipifarnib reduced cell viability in these T-cell leukemia and TCL cell lines, induced apoptosis and modified the cell cycle. A mutational study showed TP53, NOTCH1 and DNMT3 to be mutated in 84.6%, 69.2% and 30.0% of sensitive cell lines, and in 62.5%, 0% and 0% of resistant cell lines, respectively. An immunohistochemistry study showed that p-ERK and RelB were associated as potential biomarkers of tipifarnib sensitivity and resistance, respectively. Data from RNA-seq show that tipifarnib at IC50 after 72 h downregulated a great variety of pathways, including those controlling cell cycle, metabolism, and ribosomal and mitochondrial activity. This study establishes tipifarnib as a potential therapeutic option in T-cell leukemia and TCL. The mutational state of NOTCH1, p-ERK and RelB could serve as potential biomarkers of tipifarnib sensitivity and resistance.
dc.description.sponsorship The research was supported by grants from the Instituto de Salud Carlos III, from the Ministerio de Economía, Industria y Competitividad [SAF2013-47416-R, CIBERONC-ISCIII, ISCIII-MINECO-AES-FEDER (Plan Estatal I + D + I 2013–2016)}.
dc.format.mimetype application/pdf
dc.language.iso eng
dc.publisher Nature Research
dc.relation.ispartof Sci Rep. 2020; 10(1):6721
dc.rights © The Author(s) 2020. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
dc.rights.uri http://creativecommons.org/licenses/by/4.0/
dc.title Identification of tipifarnib sensitivity biomarkers in T-cell acute lymphoblastic leukemia and T-cell lymphoma
dc.type info:eu-repo/semantics/article
dc.identifier.doi http://dx.doi.org/10.1038/s41598-020-63434-5
dc.subject.keyword Biomarkers
dc.subject.keyword Cancer
dc.subject.keyword Cancer genetics
dc.subject.keyword Cancer genomics
dc.subject.keyword Genetics
dc.subject.keyword Haematological cancer
dc.subject.keyword Molecular biology
dc.subject.keyword Molecular medicine
dc.subject.keyword Oncology
dc.relation.projectID info:eu-repo/grantAgreement/ES/1PE/SAF2013-47416-R
dc.rights.accessRights info:eu-repo/semantics/openAccess
dc.type.version info:eu-repo/semantics/publishedVersion


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