β-Catenin activity induces an RNA biosynthesis program promoting therapy resistance in T-cell acute lymphoblastic leukemia

García Hernández, Violeta; Arambilet, David; Guillén, Yolanda; Lobo-Jarne, Teresa; Maqueda, Maria; Gekas, Christos; González, Jessica; Iglesias, Arnau; Vega García, Nerea; Sentís Carreras, Inés 1990-; Trincado Alonso, Juan Luis, 1987-; Márquez-López, Ian; Heyn, Holger; Camós, Mireia; Espinosa Blay, Lluís; Bigas Salvans, Anna

β-Catenin activity induces an RNA biosynthesis program promoting therapy resistance in T-cell acute lymphoblastic leukemia

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dc.contributor.author García Hernández, Violeta
dc.contributor.author Arambilet, David
dc.contributor.author Guillén, Yolanda
dc.contributor.author Lobo-Jarne, Teresa
dc.contributor.author Maqueda, Maria
dc.contributor.author Gekas, Christos
dc.contributor.author González, Jessica
dc.contributor.author Iglesias, Arnau
dc.contributor.author Vega García, Nerea
dc.contributor.author Sentís Carreras, Inés 1990-
dc.contributor.author Trincado Alonso, Juan Luis, 1987-
dc.contributor.author Márquez-López, Ian
dc.contributor.author Heyn, Holger
dc.contributor.author Camós, Mireia
dc.contributor.author Espinosa Blay, Lluís
dc.contributor.author Bigas Salvans, Anna
dc.date.accessioned 2023-03-06T07:22:29Z
dc.date.available 2023-03-06T07:22:29Z
dc.date.issued 2023
dc.description.abstract Understanding the molecular mechanisms that contribute to the appearance of chemotherapy resistant cell populations is necessary to improve cancer treatment. We have now investigated the role of β-catenin/CTNNB1 in the evolution of T-cell Acute Lymphoblastic Leukemia (T-ALL) patients and its involvement in therapy resistance. We have identified a specific gene signature that is directly regulated by β-catenin, TCF/LEF factors and ZBTB33/Kaiso in T-ALL cell lines, which is highly and significantly represented in five out of six refractory patients from a cohort of 40 children with T-ALL. By subsequent refinement of this gene signature, we found that a subset of β-catenin target genes involved with RNA-processing function are sufficient to segregate T-ALL refractory patients in three independent cohorts. We demonstrate the implication of β-catenin in RNA and protein synthesis in T-ALL and provide in vitro and in vivo experimental evidence that β-catenin is crucial for the cellular response to chemotherapy, mainly in the cellular recovery phase after treatment. We propose that combination treatments involving chemotherapy plus β-catenin inhibitors will enhance chemotherapy response and prevent disease relapse in T-ALL patients.
dc.description.sponsorship This work has been funded by Agencia Estatal de Investigación (SAF2016-75613-R and PID2019-104695RB-I00), Fundación AECC (GC16173697BIGA) and WCR (13-0064). VGH, DA and TL are recipients of Sara Borrell fellowship from ISCIII co-funded by the ESF+ (CD21/00145), FPI (BES-2017-080880) and AECC fellowship (POSTD21975LOBO), respectively.
dc.format.mimetype application/pdf
dc.identifier.citation García-Hernández V, Arambilet D, Guillén Y, Lobo-Jarne T, Maqueda M, Gekas C, González J, Iglesias A, Vega-García N, Sentís I, Trincado JL, Márquez-López I, Heyn H, Camós M, Espinosa L, Bigas A. β-Catenin activity induces an RNA biosynthesis program promoting therapy resistance in T-cell acute lymphoblastic leukemia. EMBO Mol Med. 2023 Feb 8;15(2):e16554. DOI: 10.15252/emmm.202216554
dc.identifier.doi http://dx.doi.org/10.15252/emmm.202216554
dc.identifier.issn 1757-4676
dc.identifier.uri http://hdl.handle.net/10230/56039
dc.language.iso eng
dc.publisher Wiley
dc.relation.ispartof EMBO Mol Med. 2023 Feb 8;15(2):e16554
dc.relation.projectID info:eu-repo/grantAgreement/ES/1PE/SAF2016-75613-R
dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/PID2019-104695RB-I00
dc.rights © 2023 The Authors. Published under the terms of the CC BY 4.0 license. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
dc.rights.accessRights info:eu-repo/semantics/openAccess
dc.rights.uri http://creativecommons.org/licenses/by/4.0/
dc.subject.keyword Kaiso
dc.subject.keyword RNA processing
dc.subject.keyword T-ALL
dc.subject.keyword Chemotherapy resistance
dc.subject.keyword β-catenin
dc.title β-Catenin activity induces an RNA biosynthesis program promoting therapy resistance in T-cell acute lymphoblastic leukemia
dc.type info:eu-repo/semantics/article
dc.type.version info:eu-repo/semantics/publishedVersion

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