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dc.contributor.authorPurroy, Noelia
dc.contributor.authorCarabia, Júlia
dc.contributor.authorAbrisqueta, Pau
dc.contributor.authorEgia-Mendikute, Leire
dc.contributor.authorAguiló, Meritxell
dc.contributor.authorCarpio, Cecilia
dc.contributor.authorPalacio, Carles
dc.contributor.authorCrespo, Marta
dc.contributor.authorBosch, Francesc
dc.date.accessioned2020-12-16T11:45:15Z
dc.date.available2020-12-16T11:45:15Z
dc.date.issued2017-01-03
dc.identifier.issn1949-2553
dc.identifier.urihttp://hdl.handle.net/10459.1/70102
dc.description.abstractProliferation and survival of chronic lymphocytic leukemia (CLL) cells depend on microenvironmental signals coming from lymphoid organs. One of the key players involved in the crosstalk between CLL cells and the microenvironment is the B-cell receptor (BCR). Syk protein, a tyrosine kinase essential for BCR signaling, is therefore a rational candidate for targeted therapy in CLL. Against this background, we tested the efficacy of the highly specific Syk inhibitor TAK-659 in suppressing the favorable signaling derived from the microenvironment. To ex vivo mimic the microenvironment found in the proliferation centers, we co-cultured primary CLL cells with BM stromal cells (BMSC), CD40L and CpG ODN along with BCR stimulation. In this setting, TAK-659 inhibited the microenvironment-induced activation of Syk and downstream signaling molecules, without inhibiting the protein homologue ZAP-70 in T cells. Importantly, the pro-survival, proliferative, chemoresistant and activation effects promoted by the microenvironment were abrogated by TAK-659, which furthermore blocked CLL cell migration toward BMSC, CXCL12, and CXCL13. Combination of TAK-659 with other BCR inhibitors showed synergistic effect in inducing apoptosis, and the sequential addition of TAK-659 in ibrutinib-treated CLL cells induced significantly higher cytotoxicity. These findings provide a strong rationale for the clinical development of TAK-659 in CLL.
dc.description.sponsorshipThis work was supported by research funding from the Instituto de Salud Carlos III, Fondo de Investigaciones Sanitarias (PI 11/00792, PI14/00055, F.B and PI13/00279, M.C), cofinanced by the European Regional Development Fund (ERDF) and Asociación Española Contra el Cáncer (AECC, M.C). N.P. is a recipient of a PhD fellowship granted by Institut de Recerca Vall d’Hebron. C.C. is supported by a grant from Sociedad Española de Hematología y Hemoterapia (SEHH). M.C. holds a contract from Ministerio de Economía y Competitividad (MINECO) (RYC-2012-12018).
dc.format.mimetypeapplication/pdf
dc.language.isoeng
dc.publisherImpact Journals
dc.relationMICINN/PN2008-2011/RYC-2012-12018
dc.relation.isformatofReproducció del document publicat a: https://doi.org/10.18632/oncotarget.13557
dc.relation.ispartofOncotarget, 2017, vol. 8, num. 1, p. 742-756
dc.rightscc-by (c) Purroy, Noelia et al., 2017
dc.rights.urihttp://creativecommons.org/licenses/by/3.0/es
dc.subjectCLL
dc.subjectSyk
dc.subjectMicroenvironment
dc.subjectTAK-659
dc.subjectBCR inhibitor
dc.titleInhibition of BCR Signaling Using the Syk Inhibitor TAK-659 Prevents Stroma-Mediated Signaling in Chronic Lymphocytic Leukemia Cells
dc.typeinfo:eu-repo/semantics/article
dc.date.updated2020-12-16T11:45:15Z
dc.identifier.idgrec030247
dc.type.versioninfo:eu-repo/semantics/publishedVersion
dc.rights.accessRightsinfo:eu-repo/semantics/openAccess
dc.identifier.doihttps://doi.org/10.18632/oncotarget.13557


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cc-by (c) Purroy, Noelia et al., 2017
Except where otherwise noted, this item's license is described as cc-by (c) Purroy, Noelia et al., 2017