{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T22:31:09Z","timestamp":1791585069878,"version":"4.3.4"},"reference-count":49,"publisher":"The Royal Society","issue":"7","license":[{"start":{"date-parts":[[2024,7,1]],"date-time":"2024-07-01T00:00:00Z","timestamp":1719792000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2024,7,1]],"date-time":"2024-07-01T00:00:00Z","timestamp":1719792000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["royalsocietypublishing.org"],"crossmark-restriction":true},"short-container-title":["Open Biol."],"published-print":{"date-parts":[[2024,7]]},"abstract":"<jats:p>\n                    Ewing sarcoma (EwS) is a cancer that arises in the bones and soft tissues, typically driven by the Ewing\u2019s sarcoma breakpoint region 1-Friend leukemia virus integration 1 (EWS-FLI) oncogene. Implementation of genetically modified animal models of EwS has proved difficult largely owing to EWS-FLI\u2019s high toxicity. The EWS-FLI\n                    <jats:sub>1FS<\/jats:sub>\n                    frameshift variant that circumvents toxicity but is still able to perform key oncogenic functions provided the first study model in\n                    <jats:italic>Drosophila<\/jats:italic>\n                    . However, the quest for\n                    <jats:italic>Drosophila<\/jats:italic>\n                    lines expressing full-length, unmodified EWS-FLI remained open. Here, we show that EWS-FLI\n                    <jats:sub>1FS<\/jats:sub>\n                    \u2019s lower toxicity is owed to reduced protein levels caused by its frameshifted C-terminal peptide, and report new strategies through which we have generated\n                    <jats:italic>Drosophila<\/jats:italic>\n                    lines that express full-length, unmodified EWS-FLI. Using these lines, we have found that the upregulation of transcription from GGAA-microsatellites (GGAA\u03bcSats) presents a positive linear correlation within a wide range of EWS-FLI protein concentrations. In contrast, rather counterintuitively, GGAA\u03bcSats-independent transcriptomic dysregulation presents relatively minor differences across the same range, suggesting that GGAA\u03bcSat-dependent and -independent transcriptional upregulation present different kinetics of response with regards to changing EWS-FLI protein concentration. Our results underpin the functional relevance of varying EWS-FLI expression levels and provide experimental tools to investigate, in\n                    <jats:italic>Drosophila<\/jats:italic>\n                    , the effect of the EWS-FLI \u2018high\u2019 and \u2018low\u2019 states that have been reported and are suspected to be important for EwS in humans.\n                  <\/jats:p>","DOI":"10.1098\/rsob.240043","type":"journal-article","created":{"date-parts":[[2024,7,16]],"date-time":"2024-07-16T19:05:39Z","timestamp":1721156739000},"update-policy":"https:\/\/doi.org\/10.1098\/crossmark-policy","source":"Crossref","is-referenced-by-count":6,"title":["Human EWS-FLI protein levels and neomorphic functions show a complex, function-specific dose\u2013response relationship in\n                    <i>Drosophila<\/i>"],"prefix":"10.1098","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6925-2607","authenticated-orcid":true,"given":"Serena","family":"Mahnoor","sequence":"first","affiliation":[{"name":"Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3426-4234","authenticated-orcid":true,"given":"Cristina","family":"Molnar","sequence":"additional","affiliation":[{"name":"Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5987-2570","authenticated-orcid":true,"given":"Diego","family":"Vel\u00e1zquez","sequence":"additional","affiliation":[{"name":"Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain"},{"name":"Developmental Tumor Biology Laboratory, Institut de Recerca Sant Joan de D\u00e9u, Esplugues de Llobregat, Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3789-4514","authenticated-orcid":true,"given":"Jose","family":"Reina","sequence":"additional","affiliation":[{"name":"Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8771-2312","authenticated-orcid":true,"given":"Salud","family":"Llamazares","sequence":"additional","affiliation":[{"name":"Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2867-4539","authenticated-orcid":true,"given":"Jan Peter","family":"Heinen","sequence":"additional","affiliation":[{"name":"Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9386-5980","authenticated-orcid":true,"given":"Jaume","family":"Mora","sequence":"additional","affiliation":[{"name":"Developmental Tumor Biology Laboratory, Institut de Recerca Sant Joan de D\u00e9u, Esplugues de Llobregat, Barcelona, Spain"},{"name":"Pediatric Cancer Center Barcelona (PCCB), Hospital Sant Joan de D\u00e9u, Esplugues de Llobregat, Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5259-3608","authenticated-orcid":true,"given":"Cayetano","family":"Gonzalez","sequence":"additional","affiliation":[{"name":"Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain"},{"name":"Institucio Catalana de Recerca i Estudis Avan\u00e7ats (ICREA), Barcelona, 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