Dissecting the role of TP53 alterations in del(11q) chronic lymphocytic leukemia

Quijada-Álamo, Miguel; Pérez-Carretero, Claudia; Hernández-Sánchez, María; Rodríguez-Vicente, Ana Eugenia; Herrero, Ana B.; Hernandez-Sánchez, Jesus M.; Martín-Izquierdo, Marta; Santos-Mínguez, Sandra; Rey, Mónica del; González, Teresa; Rubio, Araceli; García de Coca, Alfonso; Dávila, Julio; Hernández-Rivas, José Ángel; Parker, Helen; Strefford, Jonathan C.; Benito, Rocío; Ordóñez, José Luis

Dissecting the role of TP53 alterations in del(11q) chronic lymphocytic leukemia

Bibliographic Details
Authors:	Quijada-Álamo, Miguel, Pérez-Carretero, Claudia, Hernández-Sánchez, María, Rodríguez-Vicente, Ana Eugenia, Herrero, Ana B., Hernandez-Sánchez, Jesus M., Martín-Izquierdo, Marta, Santos-Mínguez, Sandra, Rey, Mónica del, González, Teresa, Rubio, Araceli, García de Coca, Alfonso, Dávila, Julio, Hernández-Rivas, José Ángel, Parker, Helen, Strefford, Jonathan C., Benito, Rocío, Ordóñez, José Luis
Format:	article
Status:	Published version
Publication Date:	2021
Country:	España
Institution:	Consejo Superior de Investigaciones Científicas (CSIC)
Repository:	DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:	oai:digital.csic.es:10261/261348
Online Access:	http://hdl.handle.net/10261/261348
Access Level:	Open access
Keyword:	Biomarkers Chromosomal abnormality Chronic lymphocytic leukemia CRISPR/Cas9 system Next-generation sequencing TP53 gene

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network_acronym_str	ES
network_name_str	España
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spelling	Dissecting the role of TP53 alterations in del(11q) chronic lymphocytic leukemiaQuijada-Álamo, MiguelPérez-Carretero, ClaudiaHernández-Sánchez, MaríaRodríguez-Vicente, Ana EugeniaHerrero, Ana B.Hernandez-Sánchez, Jesus M.Martín-Izquierdo, MartaSantos-Mínguez, SandraRey, Mónica delGonzález, TeresaRubio, AraceliGarcía de Coca, AlfonsoDávila, JulioHernández-Rivas, José ÁngelParker, HelenStrefford, Jonathan C.Benito, RocíoOrdóñez, José LuisHernandez-Sánchez, Jesus M.BiomarkersChromosomal abnormalityChronic lymphocytic leukemiaCRISPR/Cas9 systemNext-generation sequencingTP53 gene© 2021 The Authors.[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.Spanish Fondo de Investigaciones Sanitarias, Grant/Award Numbers: PI15/01471, PI18/01500); Fundación Memoria Don Samuel Solórzano Barruso, Grant/Award Number: RD12/0036/0069John Wiley & SonsFundación Memoria de D. Samuel Solorzano BarrusoInstituto de Salud Carlos IIIConsejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]2022202220212022info:eu-repo/semantics/articlehttp://purl.org/coar/resource_type/c_6501Publisher's versioninfo:eu-repo/semantics/publishedVersionhttp://hdl.handle.net/10261/261348reponame:DIGITAL.CSIC. Repositorio Institucional del CSICinstname:Consejo Superior de Investigaciones Científicas (CSIC)Ingléshttp://dx.doi.org/10.1002/ctm2.304Síinfo:eu-repo/semantics/openAccessoai:digital.csic.es:10261/2613482026-05-22T06:33:51Z
dc.title.none.fl_str_mv	Dissecting the role of TP53 alterations in del(11q) chronic lymphocytic leukemia
title	Dissecting the role of TP53 alterations in del(11q) chronic lymphocytic leukemia
spellingShingle	Dissecting the role of TP53 alterations in del(11q) chronic lymphocytic leukemia Quijada-Álamo, Miguel Biomarkers Chromosomal abnormality Chronic lymphocytic leukemia CRISPR/Cas9 system Next-generation sequencing TP53 gene
title_short	Dissecting the role of TP53 alterations in del(11q) chronic lymphocytic leukemia
title_full	Dissecting the role of TP53 alterations in del(11q) chronic lymphocytic leukemia
title_fullStr	Dissecting the role of TP53 alterations in del(11q) chronic lymphocytic leukemia
title_full_unstemmed	Dissecting the role of TP53 alterations in del(11q) chronic lymphocytic leukemia
title_sort	Dissecting the role of TP53 alterations in del(11q) chronic lymphocytic leukemia
dc.creator.none.fl_str_mv	Quijada-Álamo, Miguel Pérez-Carretero, Claudia Hernández-Sánchez, María Rodríguez-Vicente, Ana Eugenia Herrero, Ana B. Hernandez-Sánchez, Jesus M. Martín-Izquierdo, Marta Santos-Mínguez, Sandra Rey, Mónica del González, Teresa Rubio, Araceli García de Coca, Alfonso Dávila, Julio Hernández-Rivas, José Ángel Parker, Helen Strefford, Jonathan C. Benito, Rocío Ordóñez, José Luis Hernandez-Sánchez, Jesus M.
author	Quijada-Álamo, Miguel
author_facet	Quijada-Álamo, Miguel Pérez-Carretero, Claudia Hernández-Sánchez, María Rodríguez-Vicente, Ana Eugenia Herrero, Ana B. Hernandez-Sánchez, Jesus M. Martín-Izquierdo, Marta Santos-Mínguez, Sandra Rey, Mónica del González, Teresa Rubio, Araceli García de Coca, Alfonso Dávila, Julio Hernández-Rivas, José Ángel Parker, Helen Strefford, Jonathan C. Benito, Rocío Ordóñez, José Luis
author_role	author
author2	Pérez-Carretero, Claudia Hernández-Sánchez, María Rodríguez-Vicente, Ana Eugenia Herrero, Ana B. Hernandez-Sánchez, Jesus M. Martín-Izquierdo, Marta Santos-Mínguez, Sandra Rey, Mónica del González, Teresa Rubio, Araceli García de Coca, Alfonso Dávila, Julio Hernández-Rivas, José Ángel Parker, Helen Strefford, Jonathan C. Benito, Rocío Ordóñez, José Luis
author2_role	author author author author author author author author author author author author author author author author author
dc.contributor.none.fl_str_mv	Fundación Memoria de D. Samuel Solorzano Barruso Instituto de Salud Carlos III Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]
dc.subject.none.fl_str_mv	Biomarkers Chromosomal abnormality Chronic lymphocytic leukemia CRISPR/Cas9 system Next-generation sequencing TP53 gene
topic	Biomarkers Chromosomal abnormality Chronic lymphocytic leukemia CRISPR/Cas9 system Next-generation sequencing TP53 gene
description	© 2021 The Authors.
publishDate	2021
dc.date.none.fl_str_mv	2021 2022 2022 2022
dc.type.none.fl_str_mv	info:eu-repo/semantics/article http://purl.org/coar/resource_type/c_6501 Publisher's version info:eu-repo/semantics/publishedVersion
format	article
status_str	publishedVersion
dc.identifier.none.fl_str_mv	http://hdl.handle.net/10261/261348
url	http://hdl.handle.net/10261/261348
dc.language.none.fl_str_mv	Inglés
language_invalid_str_mv	Inglés
dc.relation.none.fl_str_mv	http://dx.doi.org/10.1002/ctm2.304 Sí
dc.rights.none.fl_str_mv	info:eu-repo/semantics/openAccess
eu_rights_str_mv	openAccess
dc.publisher.none.fl_str_mv	John Wiley & Sons
publisher.none.fl_str_mv	John Wiley & Sons
dc.source.none.fl_str_mv	reponame:DIGITAL.CSIC. Repositorio Institucional del CSIC instname:Consejo Superior de Investigaciones Científicas (CSIC)
instname_str	Consejo Superior de Investigaciones Científicas (CSIC)
reponame_str	DIGITAL.CSIC. Repositorio Institucional del CSIC
collection	DIGITAL.CSIC. Repositorio Institucional del CSIC
repository.name.fl_str_mv
repository.mail.fl_str_mv
_version_	1869404363194105856
score	15,228081

Dissecting the role of TP53 alterations in del(11q) chronic lymphocytic leukemia

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