{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,16]],"date-time":"2026-07-16T19:35:49Z","timestamp":1784230549605,"version":"3.55.0"},"reference-count":71,"publisher":"Wiley","issue":"9","license":[{"start":{"date-parts":[[2025,9,23]],"date-time":"2025-09-23T00:00:00Z","timestamp":1758585600000},"content-version":"vor","delay-in-days":22,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100005644","name":"Universit\u00e4t Salzburg","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100005644","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["J of Extracellular Vesicle"],"published-print":{"date-parts":[[2025,9]]},"abstract":"<jats:title>ABSTRACT<\/jats:title><jats:p>Acute myeloid leukaemia (AML) is a haematologic malignancy with high relapse incidence and mortality. Approximately one\u2010third of AML patients carry an fms\u2010like tyrosine kinase 3 (FLT3) mutation, often associated with GLI expression and Hedgehog signalling. AML cells shape their microenvironment into a leukaemia\u2010permissive space by releasing extracellular vesicles (EVs). EVs can transfer chemoresistance and thereby play an important role in refractory and relapsing diseases. Here, we discovered a synergistic effect of combined treatment with the FLT3 inhibitor Crenolanib and the Hedgehog pathway inhibitor HPI\u20101 in the AML cell lines MOLM\u201014 and MV4\u201011. In\u2010depth comparative proteomics revealed alterations in the cellular and the EV proteome upon single or combined inhibition of FLT3 and GLI, highlighting affected pathways. By comparing cellular and EV proteomes, we found that transport of ribosomal proteins, such as RPS26 and RPL27A, and ErbB pathway members such as GAB1, GRB2 and SHC1 to EVs, is selectively avoided upon treatment with Crenolanib. These findings were corroborated by comparative proteomics of EVs derived from AML patients and healthy donors. Ribosomal and ErbB signalling pathway proteins may play an important role in microenvironmental modulation by EVs, and Crenolanib treatment potentially acts by interfering with leukaemia niche formation.<\/jats:p>","DOI":"10.1002\/jev2.70163","type":"journal-article","created":{"date-parts":[[2025,9,23]],"date-time":"2025-09-23T14:34:52Z","timestamp":1758638092000},"source":"Crossref","is-referenced-by-count":2,"title":["Selective EV Protein Sorting and Pathway Perturbation in AML Upon Synergistic FLT3 and Hedgehog Pathway Inhibition"],"prefix":"10.1002","volume":"14","author":[{"given":"Constantin","family":"Bl\u00f6chl","sequence":"first","affiliation":[{"name":"Department of Biosciences and Medical Biology University of Salzburg  Salzburg Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabriele","family":"Bl\u00fcmel","sequence":"additional","affiliation":[{"name":"Department of Biosciences and Medical Biology University of Salzburg  Salzburg Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4795-8086","authenticated-orcid":false,"given":"Martin","family":"Wolf","sequence":"additional","affiliation":[{"name":"Cell Therapy Institute Paracelsus Medical University  Salzburg Austria"},{"name":"Austian Red Cross Research GmbH OeRK Vienna Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christof","family":"Regl","sequence":"additional","affiliation":[{"name":"Department of Biosciences and Medical Biology University of Salzburg  Salzburg Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heide\u2010Marie","family":"Binder","sequence":"additional","affiliation":[{"name":"Cell Therapy Institute Paracelsus Medical University  Salzburg Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suzana","family":"Tesanovic","sequence":"additional","affiliation":[{"name":"Department of Biosciences and Medical Biology University of Salzburg  Salzburg Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Lankes","sequence":"additional","affiliation":[{"name":"Department of Biosciences and Medical Biology University of Salzburg  Salzburg Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicole","family":"Maeding","sequence":"additional","affiliation":[{"name":"Cell Therapy Institute Paracelsus Medical University  Salzburg Austria"},{"name":"Austian Red Cross Research GmbH OeRK Vienna Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter W.","family":"Krenn","sequence":"additional","affiliation":[{"name":"Department of Biosciences and Medical Biology University of Salzburg  Salzburg Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dirk","family":"Strunk","sequence":"additional","affiliation":[{"name":"Cell Therapy Institute Paracelsus Medical University  Salzburg Austria"},{"name":"Austian Red Cross Research GmbH OeRK Vienna Austria"},{"name":"Cancer Cluster Salzburg Salzburg Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fritz","family":"Aberger","sequence":"additional","affiliation":[{"name":"Department of Biosciences and Medical Biology University of Salzburg  Salzburg Austria"},{"name":"Cancer Cluster Salzburg Salzburg Austria"},{"name":"Center for Tumor Biology and Immunology University of Salzburg  Salzburg Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8358-1880","authenticated-orcid":false,"given":"Christian G.","family":"Huber","sequence":"additional","affiliation":[{"name":"Department of Biosciences and Medical Biology University of Salzburg  Salzburg Austria"},{"name":"Cancer Cluster Salzburg Salzburg Austria"},{"name":"Center for Tumor Biology and Immunology University of Salzburg  Salzburg Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,9,23]]},"reference":[{"key":"e_1_2_11_2_1","unstructured":"R: A Language and Environment for Statistical Computing.2024. \u201cR Foundation for Statistical Computing.\u201d Accessed 2024 version 4.4.0.https:\/\/www.R\u2010project.org\/."},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12964\u2010017\u20100163\u20104"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2019.01113"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.1002\/pmic.201300485"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbapap.2019.02.005"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41388\u2010019\u20101087\u20109"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.1038\/srep35376"},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467\u2010023\u201039657\u20101"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.matbio.2017.09.001"},{"key":"e_1_2_11_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2016.10.009"},{"key":"e_1_2_11_12_1","doi-asserted-by":"publisher","DOI":"10.3390\/cells10123321"},{"key":"e_1_2_11_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.leukres.2017.09.014"},{"key":"e_1_2_11_14_1","doi-asserted-by":"publisher","DOI":"10.2741\/4811"},{"key":"e_1_2_11_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.lfs.2019.02.003"},{"key":"e_1_2_11_16_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev\u2010cellbio\u2010101512\u2010122326"},{"key":"e_1_2_11_17_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41375\u2010018\u20100312\u20109"},{"key":"e_1_2_11_18_1","doi-asserted-by":"publisher","DOI":"10.1038\/nbt.1511"},{"key":"e_1_2_11_19_1","doi-asserted-by":"publisher","DOI":"10.1080\/14789450.2017.1260450"},{"key":"e_1_2_11_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.trsl.2021.04.002"},{"key":"e_1_2_11_21_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41375\u2010018\u20100357\u20109"},{"key":"e_1_2_11_22_1","doi-asserted-by":"publisher","DOI":"10.1021\/pr070424"},{"key":"e_1_2_11_23_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra1406184"},{"key":"e_1_2_11_24_1","doi-asserted-by":"publisher","DOI":"10.3390\/cancers11121823"},{"key":"e_1_2_11_25_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.omtn.2020.06.016"},{"key":"e_1_2_11_26_1","doi-asserted-by":"publisher","DOI":"10.1002\/pmic.202400128"},{"key":"e_1_2_11_27_1","doi-asserted-by":"publisher","DOI":"10.1080\/14789450.2017.1260450"},{"key":"e_1_2_11_28_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bioactmat.2024.02.026"},{"key":"e_1_2_11_29_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2014.00160"},{"key":"e_1_2_11_30_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598\u2010017\u201014661\u2010w"},{"key":"e_1_2_11_31_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0907134106"},{"key":"e_1_2_11_32_1","doi-asserted-by":"publisher","DOI":"10.3390\/vaccines6040069"},{"key":"e_1_2_11_33_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jproteome.8b00647"},{"key":"e_1_2_11_34_1","doi-asserted-by":"publisher","DOI":"10.1074\/mcp.RA120.002169"},{"key":"e_1_2_11_35_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jproteome.4c00158"},{"key":"e_1_2_11_36_1","doi-asserted-by":"crossref","unstructured":"Korotkevich G. V.Sukhov N.Budin B.Shpak M.Artyomov andA.Sergushichev.2016. \u201cFast Gene Set Enrichment Analysis.\u201dBioRxiv.https:\/\/doi.org\/10.1101\/060012.","DOI":"10.1101\/060012"},{"key":"e_1_2_11_37_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood.2021014761"},{"key":"e_1_2_11_38_1","doi-asserted-by":"publisher","DOI":"10.1016\/bs.ctdb.2022.02.009"},{"key":"e_1_2_11_39_1","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.16304"},{"key":"e_1_2_11_40_1","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.12343"},{"key":"e_1_2_11_41_1","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.aaa5731"},{"key":"e_1_2_11_42_1","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btt285"},{"key":"e_1_2_11_43_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M112.340588"},{"key":"e_1_2_11_44_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1400272111"},{"key":"e_1_2_11_45_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tcb.2016.11.003"},{"key":"e_1_2_11_46_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms25084430"},{"key":"e_1_2_11_47_1","doi-asserted-by":"publisher","DOI":"10.1021\/ml2002423"},{"key":"e_1_2_11_48_1","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2020.00090"},{"key":"e_1_2_11_49_1","doi-asserted-by":"publisher","DOI":"10.1002\/jev2.12033"},{"key":"e_1_2_11_50_1","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.3279"},{"key":"e_1_2_11_51_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1516192"},{"key":"e_1_2_11_52_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2018.05.012"},{"key":"e_1_2_11_53_1","doi-asserted-by":"publisher","DOI":"10.1002\/adhm.202303941"},{"key":"e_1_2_11_54_1","doi-asserted-by":"crossref","unstructured":"Poupardin R. M.Wolf N.Maeding G.Fuhrmann andD.Strunk.2024.EV\u2010Checklist: A Fast Documentation Tool for Enhancing Transparency and Accessibility in Extracellular Vesicle Research.bioRxiv.https:\/\/doi.org\/10.1101\/2024.05.17.594642.","DOI":"10.1101\/2024.05.17.594642"},{"key":"e_1_2_11_55_1","doi-asserted-by":"publisher","DOI":"10.3390\/jcm11236892"},{"key":"e_1_2_11_56_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkv007"},{"key":"e_1_2_11_57_1","doi-asserted-by":"publisher","DOI":"10.1038\/cgt.2016.48"},{"key":"e_1_2_11_58_1","doi-asserted-by":"publisher","DOI":"10.3324\/haematol.2010.039743"},{"key":"e_1_2_11_59_1","doi-asserted-by":"publisher","DOI":"10.3389\/fcell.2022.944760"},{"key":"e_1_2_11_60_1","doi-asserted-by":"publisher","DOI":"10.1002\/jev2.12140"},{"key":"e_1_2_11_61_1","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.3901"},{"key":"e_1_2_11_62_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcp.27735"},{"key":"e_1_2_11_63_1","doi-asserted-by":"publisher","DOI":"10.7150\/thno.51797"},{"key":"e_1_2_11_64_1","doi-asserted-by":"crossref","unstructured":"Wang E. A.\u2010O. A. A.\u2010O.Goldberg M.Tallman et\u00a0al.2024. \u201cCrenolanib and Intensive Chemotherapy in Adults With Newly Diagnosed FLT3\u2010Mutated AML.\u201d42 no.15:1776\u20131787. (1527\u20107755 (Electronic)).https:\/\/doi.org\/10.1200\/JCO.23.01061.","DOI":"10.1200\/JCO.23.01061"},{"key":"e_1_2_11_65_1","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-4939-7219-7_1"},{"key":"e_1_2_11_66_1","doi-asserted-by":"publisher","DOI":"10.1002\/jev2.12404"},{"key":"e_1_2_11_67_1","doi-asserted-by":"publisher","DOI":"10.1002\/jev2.12207"},{"key":"e_1_2_11_68_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467\u2010021\u201026514\u20102"},{"key":"e_1_2_11_69_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpz1.90"},{"key":"e_1_2_11_70_1","doi-asserted-by":"publisher","DOI":"10.1002\/pmic.202000094"},{"key":"e_1_2_11_71_1","doi-asserted-by":"publisher","DOI":"10.1586\/epr.12.15"},{"key":"e_1_2_11_72_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.gpb.2022.01.004"}],"container-title":["Journal of Extracellular Vesicles"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/isevjournals.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/jev2.70163","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,16]],"date-time":"2025-10-16T17:21:51Z","timestamp":1760635311000},"score":1,"resource":{"primary":{"URL":"https:\/\/isevjournals.onlinelibrary.wiley.com\/doi\/10.1002\/jev2.70163"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,9]]},"references-count":71,"journal-issue":{"issue":"9","published-print":{"date-parts":[[2025,9]]}},"alternative-id":["10.1002\/jev2.70163"],"URL":"https:\/\/doi.org\/10.1002\/jev2.70163","archive":["Portico"],"relation":{},"ISSN":["2001-3078","2001-3078"],"issn-type":[{"value":"2001-3078","type":"print"},{"value":"2001-3078","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,9]]},"article-number":"e70163"}}