Metabolic plasticity is an essential requirement of acquired tyrosine kinase inhibitor resistance in Chronic myeloid leukemia

Tyrosine kinase inhibitors (TKIs) are currently the standard chemotherapeutic agents for the treatment of chronic myeloid leukemia (CML). However, due to TKI resistance acquisition in CML patients, identification of new vulnerabilities is urgently required for a sustained response to therapy. In thi...

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Autores: Contreras Mostazo, Miriam Guadalupe, Kurrle, Nina, Casado, Marta, Fuhrmann, Dominik, Alshamleh, Islam, Häupl, Björn, Martín Sanz, Paloma, Brüne, Bernhard, 1957-, Serve, Hubert, Schwalbe, Harald, Schnütgen, Frank, Marín Martínez, Silvia, Cascante i Serratosa, Marta
Formato: artículo
Estado:Versión publicada
Fecha de publicación:2020
País:España
Recursos:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
Repositorio:Recercat. Dipósit de la Recerca de Catalunya
OAI Identifier:oai:recercat.cat:2445/174562
Acesso em linha:https://hdl.handle.net/2445/174562
Access Level:acceso abierto
Palavra-chave:Leucèmia mieloide
Plasticitat
Leucèmia aguda
Metabolisme
Myeloid leukemia
Plasticity
Acute leukemia
Metabolism
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spelling Metabolic plasticity is an essential requirement of acquired tyrosine kinase inhibitor resistance in Chronic myeloid leukemiaContreras Mostazo, Miriam GuadalupeKurrle, NinaCasado, MartaFuhrmann, DominikAlshamleh, IslamHäupl, BjörnMartín Sanz, PalomaBrüne, Bernhard, 1957-Serve, HubertSchwalbe, HaraldSchnütgen, FrankMarín Martínez, SilviaCascante i Serratosa, MartaLeucèmia mieloidePlasticitatLeucèmia agudaMetabolismeMyeloid leukemiaPlasticityAcute leukemiaMetabolismTyrosine kinase inhibitors (TKIs) are currently the standard chemotherapeutic agents for the treatment of chronic myeloid leukemia (CML). However, due to TKI resistance acquisition in CML patients, identification of new vulnerabilities is urgently required for a sustained response to therapy. In this study, we have investigated metabolic reprogramming induced by TKIs independent of BCR-ABL1 alterations. Proteomics and metabolomics profiling of imatinib-resistant CML cells (ImaR) was performed. KU812 ImaR cells enhanced pentose phosphate pathway, glycogen synthesis, serine-glycine-one-carbon metabolism, proline synthesis and mitochondrial respiration compared with their respective syngeneic parental counterparts. Moreover, the fact that only 36% of the main carbon sources were utilized for mitochondrial respiration pointed to glycerol-phosphate shuttle as mainly contributors to mitochondrial respiration. In conclusion, CML cells that acquire TKIs resistance present a severe metabolic reprogramming associated with an increase in metabolic plasticity needed to overcome TKI-induced cell death. Moreover, this study unveils that KU812 Parental and ImaR cells viability can be targeted with metabolic inhibitors paving the way to propose novel and promising therapeutic opportunities to overcome TKI resistance in CML.MDPI2021202120202021info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersion26 p.application/pdfhttps://hdl.handle.net/2445/174562Articles publicats en revistes (Bioquímica i Biomedicina Molecular)reponame:Recercat. Dipósit de la Recerca de Catalunyainstname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)InglésReproducció del document publicat a: https://doi.org/10.3390/cancers12113443Cancers, 2020, vol. 12(11), num. 3443https://doi.org/10.3390/cancers12113443info:eu-repo/grantAgreement/EC/H2020/675790cc-by (c) Contreras Mostazo, Míriam G. et al., 2020http://creativecommons.org/licenses/by/3.0/esinfo:eu-repo/semantics/openAccessoai:recercat.cat:2445/1745622026-05-29T05:05:01Z
dc.title.none.fl_str_mv Metabolic plasticity is an essential requirement of acquired tyrosine kinase inhibitor resistance in Chronic myeloid leukemia
title Metabolic plasticity is an essential requirement of acquired tyrosine kinase inhibitor resistance in Chronic myeloid leukemia
spellingShingle Metabolic plasticity is an essential requirement of acquired tyrosine kinase inhibitor resistance in Chronic myeloid leukemia
Contreras Mostazo, Miriam Guadalupe
Leucèmia mieloide
Plasticitat
Leucèmia aguda
Metabolisme
Myeloid leukemia
Plasticity
Acute leukemia
Metabolism
title_short Metabolic plasticity is an essential requirement of acquired tyrosine kinase inhibitor resistance in Chronic myeloid leukemia
title_full Metabolic plasticity is an essential requirement of acquired tyrosine kinase inhibitor resistance in Chronic myeloid leukemia
title_fullStr Metabolic plasticity is an essential requirement of acquired tyrosine kinase inhibitor resistance in Chronic myeloid leukemia
title_full_unstemmed Metabolic plasticity is an essential requirement of acquired tyrosine kinase inhibitor resistance in Chronic myeloid leukemia
title_sort Metabolic plasticity is an essential requirement of acquired tyrosine kinase inhibitor resistance in Chronic myeloid leukemia
dc.creator.none.fl_str_mv Contreras Mostazo, Miriam Guadalupe
Kurrle, Nina
Casado, Marta
Fuhrmann, Dominik
Alshamleh, Islam
Häupl, Björn
Martín Sanz, Paloma
Brüne, Bernhard, 1957-
Serve, Hubert
Schwalbe, Harald
Schnütgen, Frank
Marín Martínez, Silvia
Cascante i Serratosa, Marta
author Contreras Mostazo, Miriam Guadalupe
author_facet Contreras Mostazo, Miriam Guadalupe
Kurrle, Nina
Casado, Marta
Fuhrmann, Dominik
Alshamleh, Islam
Häupl, Björn
Martín Sanz, Paloma
Brüne, Bernhard, 1957-
Serve, Hubert
Schwalbe, Harald
Schnütgen, Frank
Marín Martínez, Silvia
Cascante i Serratosa, Marta
author_role author
author2 Kurrle, Nina
Casado, Marta
Fuhrmann, Dominik
Alshamleh, Islam
Häupl, Björn
Martín Sanz, Paloma
Brüne, Bernhard, 1957-
Serve, Hubert
Schwalbe, Harald
Schnütgen, Frank
Marín Martínez, Silvia
Cascante i Serratosa, Marta
author2_role author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Leucèmia mieloide
Plasticitat
Leucèmia aguda
Metabolisme
Myeloid leukemia
Plasticity
Acute leukemia
Metabolism
topic Leucèmia mieloide
Plasticitat
Leucèmia aguda
Metabolisme
Myeloid leukemia
Plasticity
Acute leukemia
Metabolism
description Tyrosine kinase inhibitors (TKIs) are currently the standard chemotherapeutic agents for the treatment of chronic myeloid leukemia (CML). However, due to TKI resistance acquisition in CML patients, identification of new vulnerabilities is urgently required for a sustained response to therapy. In this study, we have investigated metabolic reprogramming induced by TKIs independent of BCR-ABL1 alterations. Proteomics and metabolomics profiling of imatinib-resistant CML cells (ImaR) was performed. KU812 ImaR cells enhanced pentose phosphate pathway, glycogen synthesis, serine-glycine-one-carbon metabolism, proline synthesis and mitochondrial respiration compared with their respective syngeneic parental counterparts. Moreover, the fact that only 36% of the main carbon sources were utilized for mitochondrial respiration pointed to glycerol-phosphate shuttle as mainly contributors to mitochondrial respiration. In conclusion, CML cells that acquire TKIs resistance present a severe metabolic reprogramming associated with an increase in metabolic plasticity needed to overcome TKI-induced cell death. Moreover, this study unveils that KU812 Parental and ImaR cells viability can be targeted with metabolic inhibitors paving the way to propose novel and promising therapeutic opportunities to overcome TKI resistance in CML.
publishDate 2020
dc.date.none.fl_str_mv 2020
2021
2021
2021
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv https://hdl.handle.net/2445/174562
url https://hdl.handle.net/2445/174562
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Reproducció del document publicat a: https://doi.org/10.3390/cancers12113443
Cancers, 2020, vol. 12(11), num. 3443
https://doi.org/10.3390/cancers12113443
info:eu-repo/grantAgreement/EC/H2020/675790
dc.rights.none.fl_str_mv cc-by (c) Contreras Mostazo, Míriam G. et al., 2020
http://creativecommons.org/licenses/by/3.0/es
info:eu-repo/semantics/openAccess
rights_invalid_str_mv cc-by (c) Contreras Mostazo, Míriam G. et al., 2020
http://creativecommons.org/licenses/by/3.0/es
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv 26 p.
application/pdf
dc.publisher.none.fl_str_mv MDPI
publisher.none.fl_str_mv MDPI
dc.source.none.fl_str_mv Articles publicats en revistes (Bioquímica i Biomedicina Molecular)
reponame:Recercat. Dipósit de la Recerca de Catalunya
instname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
instname_str Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
reponame_str Recercat. Dipósit de la Recerca de Catalunya
collection Recercat. Dipósit de la Recerca de Catalunya
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,812455

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