Aberrant Alternative Splicing in U2af1/Tet2 Double Mutant Mice Contributes to Major Hematological Phenotypes

16 Pág. Departamento de Reproducción Animal​

Detalhes bibliográficos
Autores: Martínez-Valiente, Cristina, Garcia-Ruiz, Cristian, Rosón, Beatriz, Liquori, Alessandro, González-Romero, Elisa, Fernández González, Raúl, Gómez-Redondo, Isabel, Cervera, José, Gutiérrez-Adán, Alfonso, Sanjuan-Pla, Alejandra
Formato: artículo
Estado:Versión publicada
Fecha de publicación:2021
País:España
Recursos:Consejo Superior de Investigaciones Científicas (CSIC)
Repositorio:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:digital.csic.es:10261/282904
Acesso em linha:http://hdl.handle.net/10261/282904
https://api.elsevier.com/content/abstract/scopus_id/85108712429
Access Level:acceso abierto
Palavra-chave:TET2
U2AF1
Alternative splicing
Myelodysplastic syndrome
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spelling Aberrant Alternative Splicing in U2af1/Tet2 Double Mutant Mice Contributes to Major Hematological PhenotypesMartínez-Valiente, CristinaGarcia-Ruiz, CristianRosón, BeatrizLiquori, AlessandroGonzález-Romero, ElisaFernández González, RaúlGómez-Redondo, IsabelCervera, JoséGutiérrez-Adán, AlfonsoSanjuan-Pla, AlejandraTET2U2AF1Alternative splicingMyelodysplastic syndrome16 Pág. Departamento de Reproducción Animal​Mutations in splicing factors are recurrent somatic alterations identified in myelodysplastic syndromes (MDS) and they frequently coincide with mutations in epigenetic factors. About 25% of patients present concurrent mutations in such pathways, suggesting a cooperative role in the pathogenesis of MDS. We focused on the splicing factor U2AF1 involved in the recognition of the 3' splice site during pre-mRNA splicing. Using a CRISPR/Cas9 system, we created heterozygous mice with a carboxy-terminal truncated U2af1 allele (U2af1mut/+), studied the U2af1mut/+ hematopoietic system, and did not observe any gross differences in both young (12-13 weeks) and old (23 months) U2af1mut/+ mice, except for a reduction in size of approximately 20%. However, hematopoietic stem/progenitor cells lacked reconstitution capacity in transplantation assays and displayed an aberrant RNA splicing by RNA sequencing. We also evaluated U2af1mut/+ in conjunction with Tet2-deficiency. Novel double mutant U2af1mut/+Tet2-/- mice showed increased monogranulocytic precursors. Hematopoietic stem/progenitor cells were also enhanced and presented functional and transcriptomic alterations. Nonetheless, U2af1mut/+Tet2-/- mice did not succumb to MDS disease over a 6-month observation period. Collectively, our data suggest that cooperation between mutant U2af1 and Tet2 loss is not sufficient for MDS initiation in mice.This work is supported by SAF2017-82171-R from the Spanish Ministry of Economy, Industry, and Competitiveness. C.M.-V. is funded by a predoctoral fellowship from Generalitat Valenciana (ACIF/2018/255). C.G.-R. is funded by AECC predoctoral fellowship. A.S.-P. is supported by the Ramón y Cajal Program (RYC2015-17534).Peer reviewedMultidisciplinary Digital Publishing InstituteMinisterio de Economía, Industria y Competitividad (España)Generalitat ValencianaAsociación Española Contra el CáncerMartínez-Valiente, Cristina [0000-0001-9332-5776]Garcia-Ruiz, Cristian [0000-0003-2914-7914]Liquori, Alessandro [0000-0002-4842-5986]González-Romero, Elisa [0000-0001-8728-295X]Fernández González, Raúl [0000-0003-1989-2945]Gómez-Redondo, Isabel [0000-0002-9319-7580]Cervera, José [0000-0001-8252-1106]Gutiérrez-Adán, Alfonso [0000-0001-9893-9179]Sanjuan-Pla, Alejandra [0000-0002-0170-5542]Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]202220222021info:eu-repo/semantics/articlehttp://purl.org/coar/resource_type/c_6501Publisher's versioninfo:eu-repo/semantics/publishedVersionhttp://hdl.handle.net/10261/282904https://api.elsevier.com/content/abstract/scopus_id/85108712429reponame:DIGITAL.CSIC. Repositorio Institucional del CSICinstname:Consejo Superior de Investigaciones Científicas (CSIC)Inglés#PLACEHOLDER_PARENT_METADATA_VALUE#info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016/SAF2017-82171-RInternational journal of molecular scienceshttps://doi.org/10.3390/ijms22136963Síinfo:eu-repo/semantics/openAccessoai:digital.csic.es:10261/2829042026-05-22T06:33:51Z
dc.title.none.fl_str_mv Aberrant Alternative Splicing in U2af1/Tet2 Double Mutant Mice Contributes to Major Hematological Phenotypes
title Aberrant Alternative Splicing in U2af1/Tet2 Double Mutant Mice Contributes to Major Hematological Phenotypes
spellingShingle Aberrant Alternative Splicing in U2af1/Tet2 Double Mutant Mice Contributes to Major Hematological Phenotypes
Martínez-Valiente, Cristina
TET2
U2AF1
Alternative splicing
Myelodysplastic syndrome
title_short Aberrant Alternative Splicing in U2af1/Tet2 Double Mutant Mice Contributes to Major Hematological Phenotypes
title_full Aberrant Alternative Splicing in U2af1/Tet2 Double Mutant Mice Contributes to Major Hematological Phenotypes
title_fullStr Aberrant Alternative Splicing in U2af1/Tet2 Double Mutant Mice Contributes to Major Hematological Phenotypes
title_full_unstemmed Aberrant Alternative Splicing in U2af1/Tet2 Double Mutant Mice Contributes to Major Hematological Phenotypes
title_sort Aberrant Alternative Splicing in U2af1/Tet2 Double Mutant Mice Contributes to Major Hematological Phenotypes
dc.creator.none.fl_str_mv Martínez-Valiente, Cristina
Garcia-Ruiz, Cristian
Rosón, Beatriz
Liquori, Alessandro
González-Romero, Elisa
Fernández González, Raúl
Gómez-Redondo, Isabel
Cervera, José
Gutiérrez-Adán, Alfonso
Sanjuan-Pla, Alejandra
author Martínez-Valiente, Cristina
author_facet Martínez-Valiente, Cristina
Garcia-Ruiz, Cristian
Rosón, Beatriz
Liquori, Alessandro
González-Romero, Elisa
Fernández González, Raúl
Gómez-Redondo, Isabel
Cervera, José
Gutiérrez-Adán, Alfonso
Sanjuan-Pla, Alejandra
author_role author
author2 Garcia-Ruiz, Cristian
Rosón, Beatriz
Liquori, Alessandro
González-Romero, Elisa
Fernández González, Raúl
Gómez-Redondo, Isabel
Cervera, José
Gutiérrez-Adán, Alfonso
Sanjuan-Pla, Alejandra
author2_role author
author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Ministerio de Economía, Industria y Competitividad (España)
Generalitat Valenciana
Asociación Española Contra el Cáncer
Martínez-Valiente, Cristina [0000-0001-9332-5776]
Garcia-Ruiz, Cristian [0000-0003-2914-7914]
Liquori, Alessandro [0000-0002-4842-5986]
González-Romero, Elisa [0000-0001-8728-295X]
Fernández González, Raúl [0000-0003-1989-2945]
Gómez-Redondo, Isabel [0000-0002-9319-7580]
Cervera, José [0000-0001-8252-1106]
Gutiérrez-Adán, Alfonso [0000-0001-9893-9179]
Sanjuan-Pla, Alejandra [0000-0002-0170-5542]
Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]
dc.subject.none.fl_str_mv TET2
U2AF1
Alternative splicing
Myelodysplastic syndrome
topic TET2
U2AF1
Alternative splicing
Myelodysplastic syndrome
description 16 Pág. Departamento de Reproducción Animal​
publishDate 2021
dc.date.none.fl_str_mv 2021
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/10261/282904
https://api.elsevier.com/content/abstract/scopus_id/85108712429
url http://hdl.handle.net/10261/282904
https://api.elsevier.com/content/abstract/scopus_id/85108712429
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv #PLACEHOLDER_PARENT_METADATA_VALUE#
info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016/SAF2017-82171-R
International journal of molecular sciences
https://doi.org/10.3390/ijms22136963
Sí
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
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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score 15.223283

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