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Dissecting the role of TP53 alterations in del(11q) chronic lymphocytic leukemia
dc.contributor.authorQuijada Álamo, Miguel 
dc.contributor.authorPérez Carretero, Claudia
dc.contributor.authorHernández-Sánchez, María
dc.contributor.authorRodríguez Vicente, Ana E. 
dc.contributor.authorHerrero, Ana Belén
dc.contributor.authorHernández Sánchez, Jesús María 
dc.contributor.authorMartín Izquierdo, Marta
dc.contributor.authorSantos Mínguez, Sandra
dc.contributor.authorDel Rey, Mónica
dc.contributor.authorGonzález, Teresa
dc.contributor.authorRubio Martínez, Araceli
dc.contributor.authorGarcía de Coca, Alfonso
dc.contributor.authorDávila Valls, Julio
dc.contributor.authorHernández Rivas, José Ángel
dc.contributor.authorParker, Helen
dc.contributor.authorStrefford, Jonathan C.
dc.contributor.authorBenito, Rocío
dc.contributor.authorOrdóñez García, José Luis 
dc.contributor.authorHernández Rivas, Jesús María 
dc.date.accessioned2024-07-11T10:24:35Z
dc.date.available2024-07-11T10:24:35Z
dc.date.issued2021
dc.identifier.citationQuijada‐Álamo, M., Pérez‐Carretero, C., Hernández‐Sánchez, M., Rodríguez‐Vicente, A.-E., Herrero, A.-B., Hernández‐Sánchez, J.-M., Martín‐Izquierdo, M., Santos‐Mínguez, S., del Rey, M., González, T., Rubio‐Martínez, A., García de Coca, A., Dávila‐Valls, J., Hernández‐Rivas, J.-Á., Parker, H., Strefford, J. C., Benito, R., Ordóñez, J.-L., & Hernández‐Rivas, J.-M. (2021). Dissecting the role of TP53 alterations in del(11q) chronic lymphocytic leukemia. Clinical and Translational Medicine, 11(2). https://doi.org/10.1002/CTM2.304es_ES
dc.identifier.urihttp://hdl.handle.net/10366/158976
dc.description[EN]Background Several genetic alterations have been identified as driver events in chronic lymphocytic leukemia (CLL) pathogenesis and oncogenic evolution. Concurrent driver alterations usually coexist within the same tumoral clone, but how the cooperation of multiple genomic abnormalities contributes to disease progression remains poorly understood. Specifically, the biological and clinical consequences of concurrent high-risk alterations such as del(11q)/ATM-mutations and del(17p)/TP53-mutations have not been established. Methods We integrated next-generation sequencing (NGS) and clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 techniques to characterize the in vitro and in vivo effects of concurrent monoallelic or biallelic ATM and/or TP53 alterations in CLL prognosis, clonal evolution, and therapy response. Results Targeted sequencing analysis of the co-occurrence of high-risk alterations in 271 CLLs revealed that biallelic inactivation of both ATM and TP53 was mutually exclusive, whereas monoallelic del(11q) and TP53 alterations significantly co-occurred in a subset of CLL patients with a highly adverse clinical outcome. We determined the biological effects of combined del(11q), ATM and/or TP53 mutations in CRISPR/Cas9-edited CLL cell lines. Our results showed that the combination of monoallelic del(11q) and TP53 mutations in CLL cells led to a clonal advantage in vitro and in in vivo clonal competition experiments, whereas CLL cells harboring biallelic ATM and TP53 loss failed to compete in in vivo xenotransplants. Furthermore, we demonstrated that CLL cell lines harboring del(11q) and TP53 mutations show only partial responses to B cell receptor signaling inhibitors, but may potentially benefit from ATR inhibition. Conclusions Our work highlights that combined monoallelic del(11q) and TP53 alterations coordinately contribute to clonal advantage and shorter overall survival in CLL.en_EN
dc.format.mimetypeapplication/pdf
dc.language.isoenges_ES
dc.publisherWiley Open Accessen_EN
dc.subjectCRISPRen_EN
dc.subjectChronic lymphocytic leukemiaen_EN
dc.subjectFarmacologíaes_ES
dc.subjectCLLes_ES
dc.subjectBCR inhibitores_ES
dc.subject.meshPharmacology *
dc.subject.meshLeukemia *
dc.subject.meshCRISPR-Cas Systems *
dc.titleDissecting the role of TP53 alterations in del(11q) chronic lymphocytic leukemiaen_EN
dc.typeinfo:eu-repo/semantics/articlees_ES
dc.relation.publishversionhttps://doi.org/10.1002/ctm2.304es_ES
dc.identifier.doi10.1002/CTM2.304
dc.rights.accessRightsinfo:eu-repo/semantics/openAccesses_ES
dc.identifier.essn2001-1326
dc.journal.titleClinical and Translational Medicineen_EN
dc.volume.number11es_ES
dc.issue.number2es_ES
dc.type.hasVersioninfo:eu-repo/semantics/publishedVersiones_ES
dc.subject.decsfarmacología *
dc.subject.decssistemas CRISPR-Cas *
dc.subject.decsleucemia *


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