A Paradoxical Tumor-Suppressor Role for the Rac1 Exchange Factor Vav1 in T Cell Acute Lymphoblastic Leukemia

Robles-Valero, Javier; Lorenzo-Martín, L. Francisco; Menacho Márquez, Mauricio; Fernández-Pisonero, Isabel; Abad, Antonio; Camós, Mireia; Toribio, María Luisa; Espinosa Blay, Lluís; Bigas Salvans, Anna; Bustelo, Xose R.

A Paradoxical Tumor-Suppressor Role for the Rac1 Exchange Factor Vav1 in T Cell Acute Lymphoblastic Leukemia

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dc.contributor.author Robles-Valero, Javierca
dc.contributor.author Lorenzo-Martín, L. Franciscoca
dc.contributor.author Menacho Márquez, Mauricioca
dc.contributor.author Fernández-Pisonero, Isabelca
dc.contributor.author Abad, Antonioca
dc.contributor.author Camós, Mireiaca
dc.contributor.author Toribio, María Luisaca
dc.contributor.author Espinosa Blay, Lluísca
dc.contributor.author Bigas Salvans, Annaca
dc.contributor.author Bustelo, Xose R.ca
dc.date.accessioned 2018-04-25T07:22:32Z
dc.date.available 2018-04-25T07:22:32Z
dc.date.issued 2017
dc.description.abstract Rho guanine exchange factors (GEFs), the enzymes that stimulate Rho GTPases, are deemed as potential therapeutic targets owing to their protumorigenic functions. However, the understanding of the spectrum of their pathobiological roles in tumors is still very limited. We report here that the GEF Vav1 unexpectedly possesses tumor-suppressor functions in immature T cells. This function entails the noncatalytic nucleation of complexes between the ubiquitin ligase Cbl-b and the intracellular domain of Notch1 (ICN1) that favors ICN1 ubiquitinylation and degradation. Ablation of Vav1 promotes ICN1 signaling and the development of T cell acute lymphoblastic leukemia (T-ALL). The downregulation of Vav1 is essential for the pathogenesis of human T-ALL of the TLX+ clinical subtype, further underscoring the suppressor role of this pathway
dc.description.sponsorship X.R.B. is supported by grants from the Castilla-León Government (BIO/SA01/15, CSI049U16), Spanish Ministry of Economy and Competitiveness (MINECO) (SAF2015-64556-R, RD12/0036/0002), Worldwide Cancer Research (14-1248), Ramón Areces Foundation, and Spanish Society Against Cancer. L.E. (PI13/00448), A.B. (SAF2013-40922-R, RD12/0036/0054), and M.L.T. (SAF2013-44857-R, RD12/0036/0075) are supported by MINECO grants. Spanish funding is partially supported by the European Regional Development Fund. We thank M. Blázquez for laboratory work, R. Valiente for ChIP-seq analyses, M. Dosil for comments on the manuscript, and CIC facilities' personnel for technical assistance
dc.format.mimetype application/pdf
dc.identifier.citation Robles-Valero J, Lorenzo-Martín LF, Menacho-Márquez M, Fernández-Pisonero I, Abad A, Camós M. et al. A Paradoxical Tumor-Suppressor Role for the Rac1 Exchange Factor Vav1 in T Cell Acute Lymphoblastic Leukemia. Cancer Cell. 2017 Nov 13;32(5):608-623.e9. DOI: 10.1016/j.ccell.2017.10.004
dc.identifier.doi http://dx.doi.org/10.1016/j.ccell.2017.10.004
dc.identifier.issn 1535-6108
dc.identifier.uri http://hdl.handle.net/10230/34442
dc.language.iso eng
dc.publisher Elsevierca
dc.relation.projectID info:eu-repo/grantAgreement/ES/1PE/SAF2015-64556-R
dc.relation.projectID info:eu-repo/grantAgreement/ES/1PE/SAF2013-40922-R
dc.relation.projectID info:eu-repo/grantAgreement/ES/1PE/SAF2013-44857-R
dc.rights.accessRights info:eu-repo/semantics/openAccess
dc.rights.uri http://creativecommons.org/licenses/by/4.0/
dc.subject.keyword Cbl-b
dc.subject.keyword Notch1
dc.subject.keyword Rho GTPases
dc.subject.keyword TLX
dc.subject.keyword Animal models
dc.subject.keyword Gene expression profiling
dc.subject.keyword Lymphoma
dc.subject.other Limfomes
dc.subject.other Leucèmia
dc.title A Paradoxical Tumor-Suppressor Role for the Rac1 Exchange Factor Vav1 in T Cell Acute Lymphoblastic Leukemiaca
dc.type info:eu-repo/semantics/article
dc.type.version info:eu-repo/semantics/publishedVersion

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