Posttranslational splicing modifications as a key mechanism in cytarabine resistance in acute myeloid leukemia

Morales, María Luz; García Vicente, Roberto; Rodrígue García, Alba; Reyes Palomares, Armando Adolfo; Vincelle Nieto, África; Álvarez, Noemí; Ortiz Ruiz, Alejandra; Garrido García, Vanesa; Giménez, Alicia; Carreño Tarragona, Gonzalo; Sánchez, Ricardo; Ayala Díaz, Rosa María; Martínez López, Joaquín; Linares Gómez, María

Posttranslational splicing modifications as a key mechanism in cytarabine resistance in acute myeloid leukemia

Despite the approval of several drugs for AML, cytarabine is still widely used as a therapeutic approach. However, 85% of patients show resistance and only 10% overcome the disease. Using RNA-seq and phosphoproteomics, we show that RNA splicing and serine-arginine-rich (SR) proteins phosphorylation...

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Autores:	Morales, María Luz, García Vicente, Roberto, Rodrígue García, Alba, Reyes Palomares, Armando Adolfo, Vincelle Nieto, África, Álvarez, Noemí, Ortiz Ruiz, Alejandra, Garrido García, Vanesa, Giménez, Alicia, Carreño Tarragona, Gonzalo, Sánchez, Ricardo, Ayala Díaz, Rosa María, Martínez López, Joaquín, Linares Gómez, María
Tipo de recurso:	artículo
Fecha de publicación:	2023
País:	España
Institución:	Universidad Complutense de Madrid (UCM)
Repositorio:	Docta Complutense
Idioma:	inglés
OAI Identifier:	oai:docta.ucm.es:20.500.14352/101903
Acceso en línea:	https://hdl.handle.net/20.500.14352/101903
Access Level:	acceso abierto
Palabra clave:	577.1 577.2 Ciencias Biomédicas Bioquímica (Farmacia) Biología molecular (Farmacia) 24 Ciencias de la Vida

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spelling	Posttranslational splicing modifications as a key mechanism in cytarabine resistance in acute myeloid leukemiaMorales, María LuzGarcía Vicente, RobertoRodrígue García, AlbaReyes Palomares, Armando AdolfoVincelle Nieto, ÁfricaÁlvarez, NoemíOrtiz Ruiz, AlejandraGarrido García, VanesaGiménez, AliciaCarreño Tarragona, GonzaloSánchez, RicardoAyala Díaz, Rosa MaríaMartínez López, JoaquínLinares Gómez, María577.1577.2Ciencias BiomédicasBioquímica (Farmacia)Biología molecular (Farmacia)24 Ciencias de la VidaDespite the approval of several drugs for AML, cytarabine is still widely used as a therapeutic approach. However, 85% of patients show resistance and only 10% overcome the disease. Using RNA-seq and phosphoproteomics, we show that RNA splicing and serine-arginine-rich (SR) proteins phosphorylation were altered during cytarabine resistance. Moreover, phosphorylation of SR proteins at diagnosis were significantly lower in responder than non-responder patients, pointing to their utility to predict response. These changes correlated with altered transcriptomic profiles of SR protein target genes. Notably, splicing inhibitors were therapeutically effective in treating sensitive and resistant AML cells as monotherapy or combination with other approved drugs. H3B-8800 and venetoclax combination showed the best efficacy in vitro, demonstrating synergistic effects in patient samples and no toxicity in healthy hematopoietic progenitors. Our results establish that RNA splicing inhibition, alone or combined with venetoclax, could be useful for the treatment of newly diagnosed or relapsed/refractory AML.Universidad Complutense de Madrid20232023-07-0820232023-07-08journal articlehttp://purl.org/coar/resource_type/c_6501AMhttp://purl.org/coar/version/c_ab4af688f83e57aainfo:eu-repo/semantics/articleapplication/pdfhttps://hdl.handle.net/20.500.14352/101903reponame:Docta Complutenseinstname:Universidad Complutense de Madrid (UCM)Inglésengopen accesshttp://purl.org/coar/access_right/c_abf2Attribution-NonCommercial-NoDerivatives 4.0 Internationalhttp://creativecommons.org/licenses/by-nc-nd/4.0/info:eu-repo/semantics/openAccessoai:docta.ucm.es:20.500.14352/1019032026-06-02T12:44:21Z
dc.title.none.fl_str_mv	Posttranslational splicing modifications as a key mechanism in cytarabine resistance in acute myeloid leukemia
title	Posttranslational splicing modifications as a key mechanism in cytarabine resistance in acute myeloid leukemia
spellingShingle	Posttranslational splicing modifications as a key mechanism in cytarabine resistance in acute myeloid leukemia Morales, María Luz 577.1 577.2 Ciencias Biomédicas Bioquímica (Farmacia) Biología molecular (Farmacia) 24 Ciencias de la Vida
title_short	Posttranslational splicing modifications as a key mechanism in cytarabine resistance in acute myeloid leukemia
title_full	Posttranslational splicing modifications as a key mechanism in cytarabine resistance in acute myeloid leukemia
title_fullStr	Posttranslational splicing modifications as a key mechanism in cytarabine resistance in acute myeloid leukemia
title_full_unstemmed	Posttranslational splicing modifications as a key mechanism in cytarabine resistance in acute myeloid leukemia
title_sort	Posttranslational splicing modifications as a key mechanism in cytarabine resistance in acute myeloid leukemia
dc.creator.none.fl_str_mv	Morales, María Luz García Vicente, Roberto Rodrígue García, Alba Reyes Palomares, Armando Adolfo Vincelle Nieto, África Álvarez, Noemí Ortiz Ruiz, Alejandra Garrido García, Vanesa Giménez, Alicia Carreño Tarragona, Gonzalo Sánchez, Ricardo Ayala Díaz, Rosa María Martínez López, Joaquín Linares Gómez, María
author	Morales, María Luz
author_facet	Morales, María Luz García Vicente, Roberto Rodrígue García, Alba Reyes Palomares, Armando Adolfo Vincelle Nieto, África Álvarez, Noemí Ortiz Ruiz, Alejandra Garrido García, Vanesa Giménez, Alicia Carreño Tarragona, Gonzalo Sánchez, Ricardo Ayala Díaz, Rosa María Martínez López, Joaquín Linares Gómez, María
author_role	author
author2	García Vicente, Roberto Rodrígue García, Alba Reyes Palomares, Armando Adolfo Vincelle Nieto, África Álvarez, Noemí Ortiz Ruiz, Alejandra Garrido García, Vanesa Giménez, Alicia Carreño Tarragona, Gonzalo Sánchez, Ricardo Ayala Díaz, Rosa María Martínez López, Joaquín Linares Gómez, María
author2_role	author author author author author author author author author author author author author
dc.contributor.none.fl_str_mv	Universidad Complutense de Madrid
dc.subject.none.fl_str_mv	577.1 577.2 Ciencias Biomédicas Bioquímica (Farmacia) Biología molecular (Farmacia) 24 Ciencias de la Vida
topic	577.1 577.2 Ciencias Biomédicas Bioquímica (Farmacia) Biología molecular (Farmacia) 24 Ciencias de la Vida
description	Despite the approval of several drugs for AML, cytarabine is still widely used as a therapeutic approach. However, 85% of patients show resistance and only 10% overcome the disease. Using RNA-seq and phosphoproteomics, we show that RNA splicing and serine-arginine-rich (SR) proteins phosphorylation were altered during cytarabine resistance. Moreover, phosphorylation of SR proteins at diagnosis were significantly lower in responder than non-responder patients, pointing to their utility to predict response. These changes correlated with altered transcriptomic profiles of SR protein target genes. Notably, splicing inhibitors were therapeutically effective in treating sensitive and resistant AML cells as monotherapy or combination with other approved drugs. H3B-8800 and venetoclax combination showed the best efficacy in vitro, demonstrating synergistic effects in patient samples and no toxicity in healthy hematopoietic progenitors. Our results establish that RNA splicing inhibition, alone or combined with venetoclax, could be useful for the treatment of newly diagnosed or relapsed/refractory AML.
publishDate	2023
dc.date.none.fl_str_mv	2023 2023-07-08 2023 2023-07-08
dc.type.none.fl_str_mv	journal article http://purl.org/coar/resource_type/c_6501 AM http://purl.org/coar/version/c_ab4af688f83e57aa
dc.type.openaire.fl_str_mv	info:eu-repo/semantics/article
format	article
dc.identifier.none.fl_str_mv	https://hdl.handle.net/20.500.14352/101903
url	https://hdl.handle.net/20.500.14352/101903
dc.language.none.fl_str_mv	Inglés eng
language_invalid_str_mv	Inglés
language	eng
dc.rights.none.fl_str_mv	open access http://purl.org/coar/access_right/c_abf2 Attribution-NonCommercial-NoDerivatives 4.0 International http://creativecommons.org/licenses/by-nc-nd/4.0/
dc.rights.openaire.fl_str_mv	info:eu-repo/semantics/openAccess
rights_invalid_str_mv	open access http://purl.org/coar/access_right/c_abf2 Attribution-NonCommercial-NoDerivatives 4.0 International http://creativecommons.org/licenses/by-nc-nd/4.0/
eu_rights_str_mv	openAccess
dc.format.none.fl_str_mv	application/pdf
dc.source.none.fl_str_mv	reponame:Docta Complutense instname:Universidad Complutense de Madrid (UCM)
instname_str	Universidad Complutense de Madrid (UCM)
reponame_str	Docta Complutense
collection	Docta Complutense
repository.name.fl_str_mv
repository.mail.fl_str_mv
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Posttranslational splicing modifications as a key mechanism in cytarabine resistance in acute myeloid leukemia

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