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Actin cytoskeleton deregulation confers midostaurin resistance in FLT3-mutant acute myeloid leukemia

dc.contributor.authorGaritano Trojaola, Andoni
dc.contributor.authorSancho Erkizia, Ana ORCID
dc.contributor.authorGötz, Ralph
dc.contributor.authorEiring, Patrick
dc.contributor.authorWalz, Susanne
dc.contributor.authorJetani, Hardikkumar
dc.contributor.authorGil-Pulido, Jesús
dc.contributor.authorDa Via, Matteo Claudio
dc.contributor.authorTeufel, Eva
dc.contributor.authorRhodes, Nadine
dc.contributor.authorHaertle, Larissa
dc.contributor.authorArellano-Viera, Estibaliz
dc.contributor.authorTibes, Raoul
dc.contributor.authorRosenwald, Andreas
dc.contributor.authorRasche, Leo
dc.contributor.authorHudecek, Michael
dc.contributor.authorSauer, Markus
dc.contributor.authorGroll, Jürgen
dc.contributor.authorEinsele, Hermann
dc.contributor.authorKraus, Sabrina
dc.contributor.authorKortüm, Martin K.
dc.date.accessioned2021-07-27T08:44:46Z
dc.date.available2021-07-27T08:44:46Z
dc.date.issued2021-06-25
dc.identifier.citationCommunications Biology 4 : (2021) // Article ID 799es_ES
dc.identifier.issn2399-3642
dc.identifier.urihttp://hdl.handle.net/10810/52575
dc.description.abstractThe presence of FMS-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD) is one of the most frequent mutations in acute myeloid leukemia (AML) and is associated with an unfavorable prognosis. FLT3 inhibitors, such as midostaurin, are used clinically but fail to entirely eradicate FLT3-ITD + AML. This study introduces a new perspective and highlights the impact of RAC1-dependent actin cytoskeleton remodeling on resistance to midostaurin in AML. RAC1 hyperactivation leads resistance via hyperphosphorylation of the positive regulator of actin polymerization N-WASP and antiapoptotic BCL-2. RAC1/N-WASP, through ARP2/3 complex activation, increases the number of actin filaments, cell stiffness and adhesion forces to mesenchymal stromal cells (MSCs) being identified as a biomarker of resistance. Midostaurin resistance can be overcome by a combination of midostaruin, the BCL-2 inhibitor venetoclax and the RAC1 inhibitor Eht1864 in midostaurin-resistant AML cell lines and primary samples, providing the first evidence of a potential new treatment approach to eradicate FLT3-ITD + AML.es_ES
dc.description.sponsorshipThis research was supported by the IZKF grant (B-334). As well, we thank Patricia Maiso Laboratory (Marta Lasa and Sarai Sarvide) for providing HS-5 cell line and the protocol for co-culturing mesenchymal stromal cells and tumor cells.es_ES
dc.language.isoenges_ES
dc.publisherNature Researches_ES
dc.rightsinfo:eu-repo/semantics/openAccesses_ES
dc.rights.urihttp://creativecommons.org/licenses/by/3.0/es/*
dc.titleActin cytoskeleton deregulation confers midostaurin resistance in FLT3-mutant acute myeloid leukemiaes_ES
dc.typeinfo:eu-repo/semantics/articlees_ES
dc.rights.holder© The Author(s) 2021 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/ licenses/by/4.0/. (cc by)es_ES
dc.rights.holderAtribución 3.0 España*
dc.relation.publisherversionhttps://rdcu.be/cpUgtes_ES
dc.identifier.doi10.1038/s42003-021-02215-w
dc.departamentoesIngeniería de sistemas y automáticaes_ES
dc.departamentoeuSistemen ingeniaritza eta automatikaes_ES


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© The Author(s) 2021 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/ licenses/by/4.0/. (cc by)
Except where otherwise noted, this item's license is described as © The Author(s) 2021 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/ licenses/by/4.0/. (cc by)