ASB2 is a direct target of FLI1 that sustains NF-κB pathway activation in germinal center-derived diffuse large B-cell lymphoma

Abstract Background 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...

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Autores principales:	Giulio Sartori, Sara Napoli, Luciano Cascione, Elaine Yee Lin Chung, Valdemar Priebe, Alberto Jesus Arribas, Afua Adjeiwaa Mensah, Michela Dall’Angelo, Chiara Falzarano, Laura Barnabei, Mattia Forcato, Andrea Rinaldi, Silvio Bicciato, Margot Thome, Francesco Bertoni
Formato:	article
Lenguaje:	EN
Publicado:	BMC 2021
Materias:	11q24.3 gain Diffuse large B-cell lymphoma (DLBCL) Transcription factor FLI1 NFKB pathway ASB2 Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
Acceso en línea:	https://doaj.org/article/490c1667e613427b8a22fd636cfa21a8
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spelling	oai:doaj.org-article:490c1667e613427b8a22fd636cfa21a82021-11-14T12:15:25ZASB2 is a direct target of FLI1 that sustains NF-κB pathway activation in germinal center-derived diffuse large B-cell lymphoma10.1186/s13046-021-02159-31756-9966https://doaj.org/article/490c1667e613427b8a22fd636cfa21a82021-11-01T00:00:00Zhttps://doi.org/10.1186/s13046-021-02159-3https://doaj.org/toc/1756-9966Abstract Background 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. Methods 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. Results Analysis of clinical DLBCL specimens showed that FLI1 gene was more frequently expressed at higher levels in GCB than in ABC DLBCL and its protein levels were higher in GCB than in ABC DLBCL cell lines. 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-κB 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-κB-associated ASB2 , a putative essential gene for DLBCL cell survival. ASB2 gene downregulation was toxic in GCB DLBCL cell lines and induced NF-κB inhibition via downregulation of RelB and increased IκBα. Additionally, downregulation of FLI1, but not ASB2, caused reduction of NF-κB1 and RelA protein levels. Conclusions We conclude that FLI1 directly regulates a network of biologically crucial genes and processes in GCB DLBCL. FLI1 regulates both the classical NF-κB pathway at the transcriptional level, and the alternative NF-κB pathway, via ASB2. FLI1 and ASB2 inhibition represents a potential novel therapeutic approach for GCB DLBCL.Giulio SartoriSara NapoliLuciano CascioneElaine Yee Lin ChungValdemar PriebeAlberto Jesus ArribasAfua Adjeiwaa MensahMichela Dall’AngeloChiara FalzaranoLaura BarnabeiMattia ForcatoAndrea RinaldiSilvio BicciatoMargot ThomeFrancesco BertoniBMCarticle11q24.3 gainDiffuse large B-cell lymphoma (DLBCL)Transcription factor FLI1NFKB pathwayASB2Neoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282ENJournal of Experimental & Clinical Cancer Research, Vol 40, Iss 1, Pp 1-12 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	11q24.3 gain Diffuse large B-cell lymphoma (DLBCL) Transcription factor FLI1 NFKB pathway ASB2 Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
spellingShingle	11q24.3 gain Diffuse large B-cell lymphoma (DLBCL) Transcription factor FLI1 NFKB pathway ASB2 Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Giulio Sartori Sara Napoli Luciano Cascione Elaine Yee Lin Chung Valdemar Priebe Alberto Jesus Arribas Afua Adjeiwaa Mensah Michela Dall’Angelo Chiara Falzarano Laura Barnabei Mattia Forcato Andrea Rinaldi Silvio Bicciato Margot Thome Francesco Bertoni ASB2 is a direct target of FLI1 that sustains NF-κB pathway activation in germinal center-derived diffuse large B-cell lymphoma
description	Abstract Background 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. Methods 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. Results Analysis of clinical DLBCL specimens showed that FLI1 gene was more frequently expressed at higher levels in GCB than in ABC DLBCL and its protein levels were higher in GCB than in ABC DLBCL cell lines. 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-κB 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-κB-associated ASB2 , a putative essential gene for DLBCL cell survival. ASB2 gene downregulation was toxic in GCB DLBCL cell lines and induced NF-κB inhibition via downregulation of RelB and increased IκBα. Additionally, downregulation of FLI1, but not ASB2, caused reduction of NF-κB1 and RelA protein levels. Conclusions We conclude that FLI1 directly regulates a network of biologically crucial genes and processes in GCB DLBCL. FLI1 regulates both the classical NF-κB pathway at the transcriptional level, and the alternative NF-κB pathway, via ASB2. FLI1 and ASB2 inhibition represents a potential novel therapeutic approach for GCB DLBCL.
format	article
author	Giulio Sartori Sara Napoli Luciano Cascione Elaine Yee Lin Chung Valdemar Priebe Alberto Jesus Arribas Afua Adjeiwaa Mensah Michela Dall’Angelo Chiara Falzarano Laura Barnabei Mattia Forcato Andrea Rinaldi Silvio Bicciato Margot Thome Francesco Bertoni
author_facet	Giulio Sartori Sara Napoli Luciano Cascione Elaine Yee Lin Chung Valdemar Priebe Alberto Jesus Arribas Afua Adjeiwaa Mensah Michela Dall’Angelo Chiara Falzarano Laura Barnabei Mattia Forcato Andrea Rinaldi Silvio Bicciato Margot Thome Francesco Bertoni
author_sort	Giulio Sartori
title	ASB2 is a direct target of FLI1 that sustains NF-κB pathway activation in germinal center-derived diffuse large B-cell lymphoma
title_short	ASB2 is a direct target of FLI1 that sustains NF-κB pathway activation in germinal center-derived diffuse large B-cell lymphoma
title_full	ASB2 is a direct target of FLI1 that sustains NF-κB pathway activation in germinal center-derived diffuse large B-cell lymphoma
title_fullStr	ASB2 is a direct target of FLI1 that sustains NF-κB pathway activation in germinal center-derived diffuse large B-cell lymphoma
title_full_unstemmed	ASB2 is a direct target of FLI1 that sustains NF-κB pathway activation in germinal center-derived diffuse large B-cell lymphoma
title_sort	asb2 is a direct target of fli1 that sustains nf-κb pathway activation in germinal center-derived diffuse large b-cell lymphoma
publisher	BMC
publishDate	2021
url	https://doaj.org/article/490c1667e613427b8a22fd636cfa21a8
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ASB2 is a direct target of FLI1 that sustains NF-κB pathway activation in germinal center-derived diffuse large B-cell lymphoma

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