{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T13:41:53Z","timestamp":1790775713843,"version":"4.1.0"},"reference-count":50,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2021,11,11]],"date-time":"2021-11-11T00:00:00Z","timestamp":1636588800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2021,11,11]],"date-time":"2021-11-11T00:00:00Z","timestamp":1636588800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"name":"Swiss Cancer Research grant","award":["KLS-3580-02-2015"],"award-info":[{"award-number":["KLS-3580-02-2015"]}]},{"DOI":"10.13039\/100004460","name":"Rotary Foundation","doi-asserted-by":"publisher","award":["GG1639200"],"award-info":[{"award-number":["GG1639200"]}],"id":[{"id":"10.13039\/100004460","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100004460","name":"Rotary Foundation","doi-asserted-by":"publisher","award":["GG1756935"],"award-info":[{"award-number":["GG1756935"]}],"id":[{"id":"10.13039\/100004460","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["J Exp Clin Cancer Res"],"abstract":"<jats:title>Abstract<\/jats:title><jats:sec>\n                <jats:title>Background<\/jats:title>\n                <jats:p>Diffuse large B-cell lymphoma (DLBCL) comprises at least two main biologically distinct entities: germinal center B-cell (GCB) and activated B-cell (ABC) subtype. Albeit sharing common lesions, GCB and ABC DLBCL present subtype-specific oncogenic pathway perturbations. ABC DLBCL is typically characterized by a constitutively active NF-kB. However, the latter is seen in also 30% of GCB DLBCL. Another recurrent lesion in DLBCL is an 11q24.3 gain, associated with the overexpression of two ETS transcription factors, ETS1 and FLI1. Here, we showed that FLI1 is more expressed in GCB than ABC DLBCL and we characterized its transcriptional network.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods<\/jats:title>\n                <jats:p>Gene expression data were obtained from public datasets GSE98588, phs001444.v2.p1, GSE95013 and GSE10846. ChIP-Seq for FLI1 paired with transcriptome analysis (RNA-Seq) after FLI1 silencing (siRNAs) was performed. Sequencing was carried out using the NextSeq 500 (Illumina). Detection of peaks was done using HOMER (v2.6); differential expressed genes were identified using moderated t-test (limma R-package) and functionally annotated with g:Profiler. ChIP-Seq and RNA-Seq data from GCB DLBCL cell lines after FLI1 downregulation were integrated to identify putative direct targets of FLI1.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>Analysis of clinical DLBCL specimens showed that FLI1\u00a0gene was more frequently expressed at higher levels in GCB than in ABC DLBCL and its\u00a0 protein levels\u00a0were higher in GCB than in ABC DLBCL cell lines<jats:bold>.<\/jats:bold> Genes negatively regulated by FLI1 included tumor suppressor genes involved in negative regulation of cell cycle and hypoxia. Among positively regulated targets of FLI1, we found genes annotated for immune response, MYC targets, NF-\u03baB and BCR signaling and NOTCH pathway genes. Of note, direct targets of FLI1 overlapped with genes regulated by ETS1, the other transcription factor gained at the 11q24.3 locus in DLBCL, suggesting a functional convergence within the ETS family. Positive targets of FLI1 included the NF-\u03baB-associated <jats:italic>ASB2<\/jats:italic> a putative essential gene for DLBCL cell survival. <jats:italic>ASB2<\/jats:italic> gene downregulation was toxic in GCB DLBCL cell lines and induced NF-\u03baB inhibition via downregulation of RelB and increased I\u03baB\u03b1. Additionally, downregulation of <jats:italic>FLI1<\/jats:italic>, but not <jats:italic>ASB2<\/jats:italic>, caused reduction of NF-\u03baB1 and RelA protein levels.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusions<\/jats:title>\n                <jats:p>We conclude that FLI1 directly regulates a network of biologically crucial genes and processes in GCB DLBCL. FLI1 regulates both the classical NF-\u03baB pathway at the transcriptional level, and the alternative NF-\u03baB pathway, via ASB2. FLI1 and ASB2 inhibition represents a potential novel therapeutic approach for GCB DLBCL.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1186\/s13046-021-02159-3","type":"journal-article","created":{"date-parts":[[2021,11,11]],"date-time":"2021-11-11T07:04:54Z","timestamp":1636614294000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["ASB2 is a direct target of FLI1 that sustains NF-\u03baB pathway activation in germinal center-derived diffuse large B-cell lymphoma"],"prefix":"10.1186","volume":"40","author":[{"given":"Giulio","family":"Sartori","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara","family":"Napoli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luciano","family":"Cascione","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elaine Yee Lin","family":"Chung","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valdemar","family":"Priebe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alberto Jesus","family":"Arribas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Afua Adjeiwaa","family":"Mensah","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michela","family":"Dall\u2019Angelo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chiara","family":"Falzarano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Barnabei","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mattia","family":"Forcato","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Rinaldi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silvio","family":"Bicciato","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Margot","family":"Thome","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5637-8983","authenticated-orcid":false,"given":"Francesco","family":"Bertoni","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,11,11]]},"reference":[{"issue":"21","key":"2159_CR1","doi-asserted-by":"publisher","first-page":"2307","DOI":"10.1182\/blood-2017-11-764332","volume":"131","author":"L Pasqualucci","year":"2018","unstructured":"Pasqualucci L, Dalla-Favera R. 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