{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,29]],"date-time":"2026-08-29T00:22:58Z","timestamp":1787962978752,"version":"build-2784847793"},"reference-count":78,"publisher":"Public Library of Science (PLoS)","issue":"3","license":[{"start":{"date-parts":[[2021,3,2]],"date-time":"2021-03-02T00:00:00Z","timestamp":1614643200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["RO1CA236389, RO1AI105114, RO3AI094054"],"award-info":[{"award-number":["RO1CA236389, RO1AI105114, RO3AI094054"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100002645","name":"Carol M. Baldwin Breast Cancer Research Fund","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100002645","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000088","name":"Ernest C. Manning Awards Foundation","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100000088","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:p>The inflammatory cytokine IL-6 is known to play a causal role in the promotion of cancer, although the underlying mechanisms remain to be completely understood. Interplay between endogenous and environmental cues determines the fate of cancer development. The E\u03bc-<jats:italic>myc<\/jats:italic> transgenic mouse expresses elevated levels of c-Myc in the B cell lineage and develops B cell lymphomas with associated mutations in p53 or other genes linked to apoptosis. We generated E\u03bc-<jats:italic>myc<\/jats:italic> mice that either lacked the IL-6 gene, or lacked the STAT3 gene specifically in B cells to determine the role of the IL-6\/JAK\/STAT3 pathway in tumor development. Using the <jats:italic>E\u03bc-myc<\/jats:italic> lymphoma mouse model, we demonstrate that IL-6 is a critical tumor promoter during early stages of B cell lymphomagenesis. IL-6 is shown to inhibit the expression of tumor suppressors, notably BIM and PTEN, and this may contribute to advancing MYC-driven B cell tumorigenesis. Several miRNAs known to target BIM and PTEN are upregulated by IL-6 and likely lead to the stable suppression of pro-apoptotic pathways early during the tumorigenic process. STAT3, a classical downstream effector of IL-6, appears dispensable for <jats:italic>E\u03bc-myc<\/jats:italic> driven lymphomagenesis. We conclude that the growth-promoting and anti-apoptotic mechanisms activated by IL-6 are critically involved in <jats:italic>E\u03bc-myc<\/jats:italic> driven tumor initiation and progression, but the B cell intrinsic expression of STAT3 is not required.<\/jats:p>","DOI":"10.1371\/journal.pone.0247394","type":"journal-article","created":{"date-parts":[[2021,3,2]],"date-time":"2021-03-02T18:28:19Z","timestamp":1614709699000},"page":"e0247394","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":11,"title":["IL-6 promotes MYC-induced B cell lymphomagenesis independent of STAT3"],"prefix":"10.1371","volume":"16","author":[{"given":"Oleksi","family":"Petrenko","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinyu","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Velasco","family":"Cimica","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patricio","family":"Mena-Taboada","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ha Youn","family":"Shin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen","family":"D\u2019Amico","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4367-6097","authenticated-orcid":true,"given":"Nancy 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snapshot of IL-6 mediated involvement","volume":"375","author":"R Bharti","year":"2016","journal-title":"Cancer Lett"},{"issue":"9","key":"pone.0247394.ref004","doi-asserted-by":"crossref","first-page":"11553","DOI":"10.1007\/s13277-016-5098-7","article-title":"Role of interleukin-6 in cancer progression and therapeutic resistance","volume":"37","author":"N Kumari","year":"2016","journal-title":"Tumour biology: the journal of the International Society for Oncodevelopmental Biology and Medicine"},{"issue":"2","key":"pone.0247394.ref005","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1016\/0092-8674(94)90333-6","article-title":"Cytokine signal transduction","volume":"76","author":"T Kishimoto","year":"1994","journal-title":"Cell"},{"issue":"Pt 1","key":"pone.0247394.ref006","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1042\/bj20030407","article-title":"Principles of interleukin [IL]-6-type cytokine signalling and its regulation","volume":"374","author":"PC Heinrich","year":"2003","journal-title":"The Biochemical journal"},{"issue":"4","key":"pone.0247394.ref007","doi-asserted-by":"crossref","first-page":"503","DOI":"10.1016\/j.immuni.2012.03.013","article-title":"The JAK-STAT pathway at twenty.","volume":"36","author":"GR Stark","year":"2012","journal-title":"Immunity"},{"issue":"7","key":"pone.0247394.ref008","doi-asserted-by":"crossref","first-page":"848","DOI":"10.1593\/neo.13706","article-title":"The IL-6\/JAK\/Stat3 feed-forward loop drives tumorigenesis and metastasis","volume":"15","author":"Q Chang","year":"2013","journal-title":"Neoplasia"},{"issue":"1","key":"pone.0247394.ref009","doi-asserted-by":"crossref","first-page":"243","DOI":"10.1084\/jem.182.1.243","article-title":"Interleukin 6 is essential for in vivo development of B lineage neoplasms","volume":"182","author":"DM Hilbert","year":"1995","journal-title":"The Journal of experimental medicine"},{"issue":"3","key":"pone.0247394.ref010","first-page":"689","article-title":"Defective development of pristane-oil-induced plasmacytomas in interleukin-6-deficient BALB\/c mice","volume":"151","author":"G Lattanzio","year":"1997","journal-title":"The American journal of pathology"},{"issue":"4","key":"pone.0247394.ref011","doi-asserted-by":"crossref","first-page":"491","DOI":"10.1016\/j.immuni.2004.07.020","article-title":"TGF-beta suppresses tumor progression in colon cancer by inhibition of IL-6 trans-signaling","volume":"21","author":"C Becker","year":"2004","journal-title":"Immunity"},{"issue":"2","key":"pone.0247394.ref012","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1016\/j.ccr.2009.01.001","article-title":"IL-6 and Stat3 are required for survival of intestinal epithelial cells and development of colitis-associated cancer","volume":"15","author":"S Grivennikov","year":"2009","journal-title":"Cancer cell"},{"issue":"3","key":"pone.0247394.ref013","doi-asserted-by":"crossref","first-page":"286","DOI":"10.1016\/j.ccr.2009.12.048","article-title":"Hepatocyte IKKbeta\/NF-kappaB inhibits tumor promotion and progression by preventing oxidative stress-driven STAT3 activation","volume":"17","author":"G He","year":"2010","journal-title":"Cancer cell"},{"issue":"4","key":"pone.0247394.ref014","doi-asserted-by":"crossref","first-page":"456","DOI":"10.1016\/j.ccr.2011.03.009","article-title":"Stat3\/Socs3 activation by IL-6 transsignaling promotes progression of pancreatic intraepithelial neoplasia and development of pancreatic cancer","volume":"19","author":"M Lesina","year":"2011","journal-title":"Cancer cell"},{"issue":"10","key":"pone.0247394.ref015","doi-asserted-by":"crossref","first-page":"e10576","DOI":"10.15252\/emmm.201910576","article-title":"The IL-6 signaling complex is a critical driver, negative prognostic factor, and therapeutic target in diffuse large B-cell lymphoma.","volume":"11","author":"H Hashwah","year":"2019","journal-title":"EMBO Mol Med"},{"issue":"6","key":"pone.0247394.ref016","doi-asserted-by":"crossref","first-page":"623","DOI":"10.1038\/nm1249","article-title":"Stat3 is required for ALK-mediated lymphomagenesis and provides a possible therapeutic target","volume":"11","author":"R Chiarle","year":"2005","journal-title":"Nature medicine"},{"issue":"14","key":"pone.0247394.ref017","doi-asserted-by":"crossref","first-page":"5020","DOI":"10.1158\/0008-5472.CAN-11-0908","article-title":"STAT3 plays a critical role in KRAS-induced pancreatic tumorigenesis","volume":"71","author":"RB Corcoran","year":"2011","journal-title":"Cancer research"},{"issue":"4","key":"pone.0247394.ref018","doi-asserted-by":"crossref","first-page":"441","DOI":"10.1016\/j.ccr.2011.03.002","article-title":"Stat3 and MMP7 contribute to pancreatic ductal adenocarcinoma initiation and progression","volume":"19","author":"A Fukuda","year":"2011","journal-title":"Cancer cell"},{"issue":"6","key":"pone.0247394.ref019","doi-asserted-by":"crossref","first-page":"1108","DOI":"10.1093\/carcin\/bgn061","article-title":"Stage-specific disruption of Stat3 demonstrates a direct requirement during both the initiation and promotion stages of mouse skin tumorigenesis","volume":"29","author":"K Kataoka","year":"2008","journal-title":"Carcinogenesis"},{"key":"pone.0247394.ref020","doi-asserted-by":"crossref","first-page":"6285","DOI":"10.1038\/ncomms7285","article-title":"Disruption of STAT3 signalling promotes KRAS-induced lung tumorigenesis","volume":"6","author":"B Grabner","year":"2015","journal-title":"Nature communications"},{"key":"pone.0247394.ref021","doi-asserted-by":"crossref","first-page":"7736","DOI":"10.1038\/ncomms8736","article-title":"STAT3 regulated ARF expression suppresses prostate cancer metastasis","volume":"6","author":"J Pencik","year":"2015","journal-title":"Nature communications"},{"issue":"22","key":"pone.0247394.ref022","doi-asserted-by":"crossref","first-page":"18182","DOI":"10.1074\/jbc.M111.328831","article-title":"Signal transducer and activator of transcription 3 [STAT3] protein suppresses adenoma-to-carcinoma transition in Apcmin\/+ mice via regulation of Snail-1 [SNAI] protein stability","volume":"287","author":"J Lee","year":"2012","journal-title":"The Journal of biological chemistry"},{"issue":"2","key":"pone.0247394.ref023","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1016\/j.ccell.2017.07.005","article-title":"Genomic Evolution of Breast Cancer Metastasis and Relapse","volume":"32","author":"LR Yates","year":"2017","journal-title":"Cancer cell"},{"issue":"17\u201318","key":"pone.0247394.ref024","doi-asserted-by":"crossref","first-page":"1175","DOI":"10.1101\/gad.311852.118","article-title":"STAT3 is a master regulator of epithelial identity and KRAS-driven tumorigenesis.","volume":"32","author":"S D\u2019Amico","year":"2018","journal-title":"Genes & development"},{"issue":"6","key":"pone.0247394.ref025","article-title":"MYC Deregulation in Primary Human Cancers.","volume":"8","author":"M Kalkat","year":"2017","journal-title":"Genes [Basel]."},{"issue":"6046","key":"pone.0247394.ref026","doi-asserted-by":"crossref","first-page":"533","DOI":"10.1038\/318533a0","article-title":"The c-myc oncogene driven by immunoglobulin enhancers induces lymphoid malignancy in transgenic mice","volume":"318","author":"JM Adams","year":"1985","journal-title":"Nature"},{"issue":"4","key":"pone.0247394.ref027","doi-asserted-by":"crossref","first-page":"1436","DOI":"10.1128\/MCB.7.4.1436","article-title":"Expression of the c-myc oncogene under control of an immunoglobulin enhancer in E mu-myc transgenic mice","volume":"7","author":"WS Alexander","year":"1987","journal-title":"Molecular and cellular biology"},{"issue":"20","key":"pone.0247394.ref028","doi-asserted-by":"crossref","first-page":"2658","DOI":"10.1101\/gad.13.20.2658","article-title":"Disruption of the ARF-Mdm2-p53 tumor suppressor pathway in Myc-induced lymphomagenesis.","volume":"13","author":"CM Eischen","year":"1999","journal-title":"Genes & development"},{"issue":"15","key":"pone.0247394.ref029","doi-asserted-by":"crossref","first-page":"2424","DOI":"10.1101\/gad.12.15.2424","article-title":"Myc signaling via the ARF tumor suppressor regulates p53-dependent apoptosis and immortalization","volume":"12","author":"F Zindy","year":"1998","journal-title":"Genes & development"},{"issue":"16","key":"pone.0247394.ref030","doi-asserted-by":"crossref","first-page":"6164","DOI":"10.1073\/pnas.0401471101","article-title":"Bim is a suppressor of Myc-induced mouse B cell leukemia","volume":"101","author":"A Egle","year":"2004","journal-title":"Proceedings of the National Academy of Sciences of the United States of America"},{"issue":"5","key":"pone.0247394.ref031","doi-asserted-by":"crossref","first-page":"995","DOI":"10.1182\/blood-2009-03-212670","article-title":"Suppression of B-cell lymphomagenesis by the BH3-only proteins Bmf and Bad","volume":"115","author":"A Frenzel","year":"2010","journal-title":"Blood"},{"issue":"5","key":"pone.0247394.ref032","doi-asserted-by":"crossref","first-page":"684","DOI":"10.1038\/cdd.2008.195","article-title":"Puma and to a lesser extent Noxa are suppressors of Myc-induced lymphomagenesis","volume":"16","author":"EM Michalak","year":"2009","journal-title":"Cell death and differentiation"},{"issue":"9","key":"pone.0247394.ref033","doi-asserted-by":"crossref","first-page":"1982","DOI":"10.1182\/blood-2008-05-156851","article-title":"Defining the target specificity of ABT-737 and synergistic antitumor activities in combination with histone deacetylase inhibitors","volume":"113","author":"KF Whitecross","year":"2009","journal-title":"Blood"},{"issue":"5","key":"pone.0247394.ref034","first-page":"575","article-title":"Lymphomagenesis in E mu-myc transgenic mice can involve ras mutations","volume":"4","author":"WS Alexander","year":"1989","journal-title":"Oncogene"},{"key":"pone.0247394.ref035","doi-asserted-by":"crossref","first-page":"14581","DOI":"10.1038\/ncomms14581","article-title":"Genomic characterisation of Emu-Myc mouse lymphomas identifies Bcor as a Myc co-operative tumour-suppressor gene","volume":"8","author":"M Lefebure","year":"2017","journal-title":"Nature communications"},{"issue":"3","key":"pone.0247394.ref036","doi-asserted-by":"crossref","first-page":"510","DOI":"10.1080\/10428194.2019.1675877","article-title":"The role of MYC in the transformation and aggressiveness of \u2019indolent\u2019 B-cell malignancies.","volume":"61","author":"D Filip","year":"2020","journal-title":"Leuk Lymphoma"},{"issue":"5","key":"pone.0247394.ref037","doi-asserted-by":"crossref","first-page":"1621","DOI":"10.1128\/MCB.21.5.1621-1632.2001","article-title":"Essential role of STAT3 in the control of the acute-phase response as revealed by inducible gene inactivation [correction of activation] in the liver","volume":"21","author":"T Alonzi","year":"2001","journal-title":"Molecular and cellular biology"},{"issue":"2","key":"pone.0247394.ref038","doi-asserted-by":"crossref","first-page":"353","DOI":"10.1084\/jem.167.2.353","article-title":"The E mu-myc transgenic mouse. A model for high-incidence spontaneous lymphoma and leukemia of early B cells","volume":"167","author":"AW Harris","year":"1988","journal-title":"The Journal of experimental medicine"},{"key":"pone.0247394.ref039","doi-asserted-by":"crossref","first-page":"3887","DOI":"10.1038\/ncomms4887","article-title":"A pan-cancer proteomic perspective on The Cancer Genome Atlas","volume":"5","author":"R Akbani","year":"2014","journal-title":"Nature communications"},{"key":"pone.0247394.ref040","doi-asserted-by":"crossref","first-page":"D153","DOI":"10.1093\/nar\/gku1215","article-title":"DIANA-TarBase v7.0: indexing more than half a million experimentally supported miRNA:mRNA interactions","volume":"43","author":"IS Vlachos","year":"2015","journal-title":"Nucleic acids research"},{"issue":"20","key":"pone.0247394.ref041","doi-asserted-by":"crossref","first-page":"8525","DOI":"10.1158\/0008-5472.CAN-08-1329","article-title":"Utilization of pathway signatures to reveal distinct types of B lymphoma in the Emicro-myc model and human diffuse large B-cell lymphoma","volume":"68","author":"S Mori","year":"2008","journal-title":"Cancer research"},{"issue":"6469","key":"pone.0247394.ref042","doi-asserted-by":"crossref","first-page":"339","DOI":"10.1038\/368339a0","article-title":"Impaired immune and acute-phase responses in interleukin-6-deficient mice","volume":"368","author":"M Kopf","year":"1994","journal-title":"Nature"},{"issue":"17\u201318","key":"pone.0247394.ref043","doi-asserted-by":"crossref","first-page":"1117","DOI":"10.1101\/gad.327163.119","article-title":"Programming for T-lymphocyte fates: modularity and mechanisms.","volume":"33","author":"EV Rothenberg","year":"2019","journal-title":"Genes & development"},{"issue":"10","key":"pone.0247394.ref044","doi-asserted-by":"crossref","first-page":"a016295","DOI":"10.1101\/cshperspect.a016295","article-title":"IL-6 in inflammation, immunity, and disease.","volume":"6","author":"T Tanaka","year":"2014","journal-title":"Cold Spring Harb Perspect Biol."},{"issue":"6299","key":"pone.0247394.ref045","doi-asserted-by":"crossref","first-page":"331","DOI":"10.1038\/348331a0","article-title":"Novel primitive lymphoid tumours induced in transgenic mice by cooperation between myc and bcl-2","volume":"348","author":"A Strasser","year":"1990","journal-title":"Nature"},{"issue":"5","key":"pone.0247394.ref046","doi-asserted-by":"crossref","first-page":"347","DOI":"10.1093\/intimm\/dxq030","article-title":"IL-6: from its discovery to clinical applications","volume":"22","author":"T. Kishimoto","year":"2010","journal-title":"International immunology"},{"issue":"6","key":"pone.0247394.ref047","doi-asserted-by":"crossref","first-page":"3194","DOI":"10.4049\/jimmunol.171.6.3194","article-title":"IL-6 induces NF-kappa B activation in the intestinal epithelia","volume":"171","author":"L Wang","year":"2003","journal-title":"J Immunol"},{"issue":"4","key":"pone.0247394.ref048","doi-asserted-by":"crossref","first-page":"693","DOI":"10.1016\/j.cell.2009.10.014","article-title":"An epigenetic switch involving NF-kappaB, Lin28, Let-7 MicroRNA, and IL6 links inflammation to cell transformation","volume":"139","author":"D Iliopoulos","year":"2009","journal-title":"Cell"},{"issue":"41","key":"pone.0247394.ref049","doi-asserted-by":"crossref","first-page":"6231","DOI":"10.1038\/sj.onc.1208779","article-title":"Nfkb 1 is dispensable for Myc-induced lymphomagenesis","volume":"24","author":"U Keller","year":"2005","journal-title":"Oncogene"},{"issue":"12","key":"pone.0247394.ref050","doi-asserted-by":"crossref","first-page":"2448","DOI":"10.1182\/blood-2008-09-181008","article-title":"The IKK2\/NF-{kappa}B pathway suppresses MYC-induced lymphomagenesis","volume":"114","author":"K Klapproth","year":"2009","journal-title":"Blood"},{"key":"pone.0247394.ref051","doi-asserted-by":"crossref","first-page":"348","DOI":"10.1186\/1471-2407-10-348","article-title":"Myc suppression of Nfkb2 accelerates lymphomagenesis","volume":"10","author":"U Keller","year":"2010","journal-title":"BMC cancer"},{"issue":"6","key":"pone.0247394.ref052","doi-asserted-by":"crossref","first-page":"1317","DOI":"10.1093\/nar\/25.6.1317","article-title":"B lymphocyte-specific, Cre-mediated mutagenesis in mice","volume":"25","author":"RC Rickert","year":"1997","journal-title":"Nucleic acids research"},{"issue":"21","key":"pone.0247394.ref053","doi-asserted-by":"crossref","first-page":"2607","DOI":"10.1038\/sj.onc.1203478","article-title":"Roles of STAT3 defined by tissue-specific gene targeting","volume":"19","author":"S. Akira","year":"2000","journal-title":"Oncogene"},{"issue":"3","key":"pone.0247394.ref054","doi-asserted-by":"crossref","first-page":"1085","DOI":"10.1182\/blood-2005-07-2871","article-title":"Critical role for Stat3 in T-dependent terminal differentiation of IgG B cells","volume":"107","author":"JL Fornek","year":"2006","journal-title":"Blood"},{"issue":"4","key":"pone.0247394.ref055","doi-asserted-by":"crossref","DOI":"10.1128\/mBio.00723-16","article-title":"Ablation of STAT3 in the B Cell Compartment Restricts Gammaherpesvirus Latency In Vivo.","volume":"7","author":"SS Reddy","year":"2016","journal-title":"mBio"},{"issue":"1","key":"pone.0247394.ref056","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1038\/nn.2467","article-title":"A robust and high-throughput Cre reporting and characterization system for the whole mouse brain","volume":"13","author":"L Madisen","year":"2010","journal-title":"Nature neuroscience"},{"issue":"20","key":"pone.0247394.ref057","doi-asserted-by":"crossref","first-page":"2670","DOI":"10.1101\/gad.13.20.2670","article-title":"INK4a\/ARF mutations accelerate lymphomagenesis and promote chemoresistance by disabling p53","volume":"13","author":"CA Schmitt","year":"1999","journal-title":"Genes & development"},{"issue":"7052","key":"pone.0247394.ref058","doi-asserted-by":"crossref","first-page":"807","DOI":"10.1038\/nature03845","article-title":"Evasion of the p53 tumour surveillance network by tumour-derived MYC mutants","volume":"436","author":"MT Hemann","year":"2005","journal-title":"Nature"},{"issue":"24","key":"pone.0247394.ref059","doi-asserted-by":"crossref","first-page":"2806","DOI":"10.1101\/gad.1872909","article-title":"Genetic dissection of the miR-17~92 cluster of microRNAs in Myc-induced B-cell lymphomas.","volume":"23","author":"P Mu","year":"2009","journal-title":"Genes & development"},{"issue":"24","key":"pone.0247394.ref060","doi-asserted-by":"crossref","first-page":"2839","DOI":"10.1101\/gad.1861409","article-title":"miR-19 is a key oncogenic component of mir-17-92","volume":"23","author":"V Olive","year":"2009","journal-title":"Genes & development"},{"issue":"6","key":"pone.0247394.ref061","doi-asserted-by":"crossref","first-page":"568","DOI":"10.1177\/1947601910377491","article-title":"Myc: Maestro of MicroRNAs.","volume":"1","author":"TV Bui","year":"2010","journal-title":"Genes Cancer"},{"issue":"3","key":"pone.0247394.ref062","doi-asserted-by":"crossref","first-page":"262","DOI":"10.1097\/PPO.0b013e318258b60a","article-title":"The microRNA-17-92 family of microRNA clusters in development and disease","volume":"18","author":"CP Concepcion","year":"2012","journal-title":"Cancer J"},{"issue":"12","key":"pone.0247394.ref063","doi-asserted-by":"crossref","first-page":"1603","DOI":"10.1038\/cdd.2013.125","article-title":"The miR-17\/92 cluster: a comprehensive update on its genomics, genetics, functions and increasingly important and numerous roles in health and disease","volume":"20","author":"E Mogilyansky","year":"2013","journal-title":"Cell Death Differ"},{"issue":"1","key":"pone.0247394.ref064","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1101\/gad.1887110","article-title":"Tumorigenicity of the miR-17-92 cluster distilled","volume":"24","author":"G van Haaften","year":"2010","journal-title":"Genes & development"},{"issue":"26","key":"pone.0247394.ref065","doi-asserted-by":"crossref","first-page":"4174","DOI":"10.1038\/sj.onc.1208600","article-title":"Recurrent chromosomal aberrations in INK4a\/ARF defective primary lymphomas predict drug responses in vivo","volume":"24","author":"A Helmrich","year":"2005","journal-title":"Oncogene"},{"issue":"1","key":"pone.0247394.ref066","doi-asserted-by":"crossref","first-page":"82","DOI":"10.1158\/2159-8290.CD-12-0404","article-title":"The mTORC1 inhibitor everolimus prevents and treats Emu-Myc lymphoma by restoring oncogene-induced senescence","volume":"3","author":"M Wall","year":"2013","journal-title":"Cancer discovery"},{"issue":"23","key":"pone.0247394.ref067","doi-asserted-by":"crossref","first-page":"2419","DOI":"10.1056\/NEJMoa055351","article-title":"A biologic definition of Burkitt\u2019s lymphoma from transcriptional and genomic profiling","volume":"354","author":"M Hummel","year":"2006","journal-title":"The New England journal of medicine"},{"issue":"15","key":"pone.0247394.ref068","doi-asserted-by":"crossref","first-page":"1758","DOI":"10.1101\/gad.197590.112","article-title":"Context-specific roles for paracrine IL-6 in lymphomagenesis","volume":"26","author":"LA Gilbert","year":"2012","journal-title":"Genes & development"},{"issue":"46","key":"pone.0247394.ref069","doi-asserted-by":"crossref","first-page":"E7260","DOI":"10.1073\/pnas.1610970113","article-title":"Epigenetic gene regulation by Janus kinase 1 in diffuse large B-cell lymphoma","volume":"113","author":"L Rui","year":"2016","journal-title":"Proceedings of the National Academy of Sciences of the United States of America"},{"issue":"5","key":"pone.0247394.ref070","doi-asserted-by":"crossref","first-page":"679","DOI":"10.1038\/s41591-018-0016-8","article-title":"Molecular subtypes of diffuse large B cell lymphoma are associated with distinct pathogenic mechanisms and outcomes","volume":"24","author":"B Chapuy","year":"2018","journal-title":"Nature medicine"},{"issue":"15","key":"pone.0247394.ref071","doi-asserted-by":"crossref","first-page":"1396","DOI":"10.1056\/NEJMoa1801445","article-title":"Genetics and Pathogenesis of Diffuse Large B-Cell Lymphoma","volume":"378","author":"R Schmitz","year":"2018","journal-title":"N Engl J Med"},{"key":"pone.0247394.ref072","doi-asserted-by":"crossref","first-page":"351","DOI":"10.1146\/annurev-biochem-060308-103103","article-title":"Regulation of mRNA translation and stability by 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