Mice Overexpressing Wild-Type RRAS2 Are a Novel Model for Preclinical Testing of Anti-Chronic Lymphocytic Leukemia Therapies

B-cell chronic lymphocytic leukemia (B-CLL) is the most common type of leukemia in the Western world. Mutation in different genes, such as TP53 and ATM, and deletions at specific chromosomic regions, among which are 11q or 17p, have been described to be associated to worse disease prognosis. Recent...

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Autores: Hortal, Alejandro, Villanueva, Ana, Arellano Rojo, Irene, Prieto López, Cristina, Mendoza, Pilar, Bustelo, Xosé R., Alarcón, Balbino
Formato: artículo
Estado:Versión publicada
Fecha de publicación:2023
País:España
Recursos:Consejo Superior de Investigaciones Científicas (CSIC)
Repositorio:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:digital.csic.es:10261/341581
Acesso em linha:http://hdl.handle.net/10261/341581
Access Level:acceso abierto
Palavra-chave:R-RAS2
RAS
GTPases
Chronic lymphocytic leukemia
B-CLL
Mouse model
Ibrutinib
Venetoclax
New therapies
Cancer treatment
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spelling Mice Overexpressing Wild-Type RRAS2 Are a Novel Model for Preclinical Testing of Anti-Chronic Lymphocytic Leukemia TherapiesHortal, AlejandroVillanueva, AnaArellano Rojo, IrenePrieto López, CristinaMendoza, PilarBustelo, Xosé R.Alarcón, BalbinoR-RAS2RASGTPasesChronic lymphocytic leukemiaB-CLLMouse modelIbrutinibVenetoclaxNew therapiesCancer treatmentB-cell chronic lymphocytic leukemia (B-CLL) is the most common type of leukemia in the Western world. Mutation in different genes, such as TP53 and ATM, and deletions at specific chromosomic regions, among which are 11q or 17p, have been described to be associated to worse disease prognosis. Recent research from our group has demonstrated that, contrary to what is the usual cancer development process through missense mutations, B-CLL is driven by the overexpression of the small GTPase RRAS2 in its wild-type form without activating mutations. Some mouse models of this disease have been developed to date and are commonly used in B-CLL research, but they present different disadvantages such as the long waiting period until the leukemia fully develops, the need to do cell engraftment or, in some cases, the fact that the model does not recapitulate the alterations found in human patients. We have recently described Rosa26-RRAS2fl/flxmb1-Cre as a new mouse model of B-CLL with a full penetrance of the disease. In this work, we have validated this mouse model as a novel tool for the development of new therapies for B-CLL, by testing two of the most broadly applied targeted agents: ibrutinib and venetoclax. This also opens the door to new targeted agents against R-RAS2 itself, an approach not yet explored in the clinic.This work was supported by grants from the Spanish Association against Cancer (GC16173472GARC), Grant PID2019-104935RB-I00 from the ‘Ministerio de Ciencia y Tecnología’, Grant PID2022-136745OB-I00 funded by AEI/10.13039/501100011033 and, by the “European Union NextGenerationEU/PRTR”; Grant P2022/BMD7209 (INTEGRAMUNE-CM) from the ‘Comunidad de Madrid’, the ‘Fundación Ramón Areces’, Instituto de Salud Carlos III (ISCIII: CIBERONC–groups CB16/12/00233, CB16/12/00351), the Health Council of the Junta de Castilla y León (GRS 2036/A/19) and Gilead (GLD15/00348). The publication is part of the project PDC2021-121170-I00 “Leukomodel”, funded by the Spanish State Research Agency (AEI/10.13039/501100011033) and by the European Union under the “NextGenerationEU” program/PRTR.Peer reviewedMultidisciplinary Digital Publishing InstituteAsociación Española Contra el CáncerMinisterio de Ciencia y Tecnología (España)Ministerio de Ciencia e Innovación (España)Agencia Estatal de Investigación (España)Comunidad de MadridFundación Ramón ArecesInstituto de Salud Carlos IIIJunta de Castilla y LeónEuropean CommissionConsejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]2024202420232024info:eu-repo/semantics/articlehttp://purl.org/coar/resource_type/c_6501Publisher's versioninfo:eu-repo/semantics/publishedVersionapplication/pdfhttp://hdl.handle.net/10261/341581reponame:DIGITAL.CSIC. Repositorio Institucional del CSICinstname:Consejo Superior de Investigaciones Científicas (CSIC)Inglés#PLACEHOLDER_PARENT_METADATA_VALUE##PLACEHOLDER_PARENT_METADATA_VALUE##PLACEHOLDER_PARENT_METADATA_VALUE##PLACEHOLDER_PARENT_METADATA_VALUE#info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/PID2019-104935RB-I00info:eu-repo/grantAgreement/AEI//PID2022-136745OB-I00P2022/BMD7209/INTEGRAMUNE-CMinfo:eu-repo/grantAgreement/AEI//PDC2021-121170-I00https://doi.org/10.3390/cancers15245817Síinfo:eu-repo/semantics/openAccessoai:digital.csic.es:10261/3415812026-05-22T06:33:51Z
dc.title.none.fl_str_mv Mice Overexpressing Wild-Type RRAS2 Are a Novel Model for Preclinical Testing of Anti-Chronic Lymphocytic Leukemia Therapies
title Mice Overexpressing Wild-Type RRAS2 Are a Novel Model for Preclinical Testing of Anti-Chronic Lymphocytic Leukemia Therapies
spellingShingle Mice Overexpressing Wild-Type RRAS2 Are a Novel Model for Preclinical Testing of Anti-Chronic Lymphocytic Leukemia Therapies
Hortal, Alejandro
R-RAS2
RAS
GTPases
Chronic lymphocytic leukemia
B-CLL
Mouse model
Ibrutinib
Venetoclax
New therapies
Cancer treatment
title_short Mice Overexpressing Wild-Type RRAS2 Are a Novel Model for Preclinical Testing of Anti-Chronic Lymphocytic Leukemia Therapies
title_full Mice Overexpressing Wild-Type RRAS2 Are a Novel Model for Preclinical Testing of Anti-Chronic Lymphocytic Leukemia Therapies
title_fullStr Mice Overexpressing Wild-Type RRAS2 Are a Novel Model for Preclinical Testing of Anti-Chronic Lymphocytic Leukemia Therapies
title_full_unstemmed Mice Overexpressing Wild-Type RRAS2 Are a Novel Model for Preclinical Testing of Anti-Chronic Lymphocytic Leukemia Therapies
title_sort Mice Overexpressing Wild-Type RRAS2 Are a Novel Model for Preclinical Testing of Anti-Chronic Lymphocytic Leukemia Therapies
dc.creator.none.fl_str_mv Hortal, Alejandro
Villanueva, Ana
Arellano Rojo, Irene
Prieto López, Cristina
Mendoza, Pilar
Bustelo, Xosé R.
Alarcón, Balbino
author Hortal, Alejandro
author_facet Hortal, Alejandro
Villanueva, Ana
Arellano Rojo, Irene
Prieto López, Cristina
Mendoza, Pilar
Bustelo, Xosé R.
Alarcón, Balbino
author_role author
author2 Villanueva, Ana
Arellano Rojo, Irene
Prieto López, Cristina
Mendoza, Pilar
Bustelo, Xosé R.
Alarcón, Balbino
author2_role author
author
author
author
author
author
dc.contributor.none.fl_str_mv Asociación Española Contra el Cáncer
Ministerio de Ciencia y Tecnología (España)
Ministerio de Ciencia e Innovación (España)
Agencia Estatal de Investigación (España)
Comunidad de Madrid
Fundación Ramón Areces
Instituto de Salud Carlos III
Junta de Castilla y León
European Commission
Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]
dc.subject.none.fl_str_mv R-RAS2
RAS
GTPases
Chronic lymphocytic leukemia
B-CLL
Mouse model
Ibrutinib
Venetoclax
New therapies
Cancer treatment
topic R-RAS2
RAS
GTPases
Chronic lymphocytic leukemia
B-CLL
Mouse model
Ibrutinib
Venetoclax
New therapies
Cancer treatment
description B-cell chronic lymphocytic leukemia (B-CLL) is the most common type of leukemia in the Western world. Mutation in different genes, such as TP53 and ATM, and deletions at specific chromosomic regions, among which are 11q or 17p, have been described to be associated to worse disease prognosis. Recent research from our group has demonstrated that, contrary to what is the usual cancer development process through missense mutations, B-CLL is driven by the overexpression of the small GTPase RRAS2 in its wild-type form without activating mutations. Some mouse models of this disease have been developed to date and are commonly used in B-CLL research, but they present different disadvantages such as the long waiting period until the leukemia fully develops, the need to do cell engraftment or, in some cases, the fact that the model does not recapitulate the alterations found in human patients. We have recently described Rosa26-RRAS2fl/flxmb1-Cre as a new mouse model of B-CLL with a full penetrance of the disease. In this work, we have validated this mouse model as a novel tool for the development of new therapies for B-CLL, by testing two of the most broadly applied targeted agents: ibrutinib and venetoclax. This also opens the door to new targeted agents against R-RAS2 itself, an approach not yet explored in the clinic.
publishDate 2023
dc.date.none.fl_str_mv 2023
2024
2024
2024
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/10261/341581
url http://hdl.handle.net/10261/341581
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv #PLACEHOLDER_PARENT_METADATA_VALUE#
#PLACEHOLDER_PARENT_METADATA_VALUE#
#PLACEHOLDER_PARENT_METADATA_VALUE#
#PLACEHOLDER_PARENT_METADATA_VALUE#
info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/PID2019-104935RB-I00
info:eu-repo/grantAgreement/AEI//PID2022-136745OB-I00
P2022/BMD7209/INTEGRAMUNE-CM
info:eu-repo/grantAgreement/AEI//PDC2021-121170-I00
https://doi.org/10.3390/cancers15245817
Sí
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv Multidisciplinary Digital Publishing Institute
publisher.none.fl_str_mv Multidisciplinary Digital Publishing Institute
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
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