{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,7]],"date-time":"2026-11-07T10:29:25Z","timestamp":1794047365323,"version":"4.8.0"},"reference-count":48,"publisher":"Ferrata Storti Foundation (Haematologica)","issue":"9","license":[{"start":{"date-parts":[[2020,8,13]],"date-time":"2020-08-13T00:00:00Z","timestamp":1597276800000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["haematol"],"abstract":"<jats:p>Recent randomized trials focused on gene expression-based determination of the cell of origin in diffuse large B-cell lymphoma could not show significant improvements by adding novel agents to standard chemoimmunotherapy. The aim of this study was the identification of a gene signature able to refine current prognostication algorithms and applicable to clinical practice. Here we used a targeted gene expression profiling panel combining the Lymph2Cx signature for cell of origin classification with additional targets including MYC, BCL-2 and NFKBIA, in 186 patients from 2 randomized trials (discovery cohort) (NCT00355199 and NCT00499018). Data were validated in 3 independent series (2 large public datasets and a real-life cohort). By integrating the cell of origin, MYC\/BCL-2 double expressor status and NFKBIA expression, we defined a 3-gene signature combining MYC, BCL-2 and NFKBIA (MBN-signature), which outperformed the MYC\/BCL-2 double expressor status in multivariate analysis, and allowed further risk stratification within the germinal center B-cell\/unclassified subset. The high-risk (MBN Sig-high) subgroup identified the vast majority of double hit cases and a significant fraction of Activated B-Cell-derived diffuse large B-cell lymphomas. These results were validated in 3 independent series including a cohort from the REMoDL-B trial, where, in an exploratory ad hoc analysis, the addition of bortezomib in the MBN Sig-high subgroup provided a progression free survival advantage compared with standard chemoimmunotherapy. These data indicate that a simple 3-gene signature based on MYC, BCL-2 and NFKBIA could refine the prognostic stratification in diffuse large B-cell lymphoma, and might be the basis for future precision-therapy approaches.<\/jats:p>","DOI":"10.3324\/haematol.2019.236455","type":"journal-article","created":{"date-parts":[[2020,8,13]],"date-time":"2020-08-13T09:55:28Z","timestamp":1597312528000},"page":"2405-2416","source":"Crossref","is-referenced-by-count":10,"title":["A three-gene signature based on &lt;i&gt;MYC&lt;\/i&gt;, &lt;i&gt;BCL-2&lt;\/i&gt; and &lt;i&gt;NFKBIA&lt;\/i&gt; improves risk stratification in diffuse large B-cell lymphoma"],"prefix":"10.3324","volume":"106","author":[{"family":"Enrico Derenzini","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"family":"Saveria Mazzara","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"family":"Federica Melle","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"family":"Giovanna Motta","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"family":"Marco Fabbri","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"family":"Riccardo Bruna","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"family":"Claudio Agostinelli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"family":"Alessandra Cesano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"family":"Chiara Antonia Corsini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"family":"Ning Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"family":"Simona Righi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"family":"Elena Sabattini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"family":"Annalisa Chiappella","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"family":"Angelica Calleri","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"family":"Stefano Fiori","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"family":"Valentina Tabanelli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"family":"Antonello Cabras","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"family":"Giancarlo Pruneri","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"family":"Umberto Vitolo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"family":"Alessandro Massimo Gianni","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"family":"Alessandro Rambaldi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"family":"Paolo Corradini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"family":"Pier Luigi Zinzani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"family":"Corrado Tarella","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"family":"Stefano Pileri","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1856","published-online":{"date-parts":[[2020,8,13]]},"reference":[{"key":"28963","doi-asserted-by":"crossref","unstructured":"Alizadeh AA, Eisen MB, Davis RE. Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling. Nature. 2000; 403(6769):503-511.","DOI":"10.1038\/35000501"},{"key":"28964","doi-asserted-by":"crossref","unstructured":"Shipp MA, Ross KN, Tamayo P. Diffuse large B-cell lymphoma outcome prediction by gene-expression profiling and supervised machine learning. Nat Med. 2002; 8(1):68-74.","DOI":"10.1038\/nm0102-68"},{"key":"28965","doi-asserted-by":"crossref","unstructured":"Davis RE, Brown KD, Siebenlist U, Staudt LM. Constitutive nuclear factor kappaB activity is required for survival of activated B cell-like diffuse large B cell lymphoma cells. J Exp Med. 2001; 194(12):1861-1874.","DOI":"10.1084\/jem.194.12.1861"},{"key":"28966","doi-asserted-by":"crossref","unstructured":"Hans CP, Weisenburger DD, Greiner TC. Confirmation of the molecular classification of diffuse large B-cell lymphoma by immunohistochemistry using a tissue microarray. 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Leuk Res. 2012; 36(4):413-417.","DOI":"10.1016\/j.leukres.2011.12.012"},{"key":"28970","doi-asserted-by":"crossref","unstructured":"Coutinho R, Clear AJ, Owen A. Poor concordance among nine immunohistochemistry classifiers of cell-of-origin for diffuse large B-cell lymphoma: implications for therapeutic strategies. Clin Cancer Res. 2013; 19(24):6686-6695.","DOI":"10.1158\/1078-0432.CCR-13-1482"},{"key":"28971","doi-asserted-by":"crossref","unstructured":"Hu S, Xu-Monette ZY, Tzankov A. MYC\/BCL2 protein coexpression contributes to the inferior survival of activated Bcell subtype of diffuse large B-cell lymphoma and demonstrates high-risk gene expression signatures: a report from The International DLBCL Rituximab-CHOP Consortium Program. Blood. 2013; 121(20):4021-4031.","DOI":"10.1182\/blood-2012-10-460063"},{"key":"28972","doi-asserted-by":"crossref","unstructured":"Reinke S, Richter J, Fend F. Round-robin test for the cell-of-origin classification of diffuse large B-cell lymphoma-a feasibility study using full slide staining. Virchows Arch. 2018; 473(3):341-349.","DOI":"10.1007\/s00428-018-2367-4"},{"key":"28973","doi-asserted-by":"crossref","unstructured":"Scott DW, Wright GW, Williams PM. Determining cell-of-origin subtypes of diffuse large B-cell lymphoma using gene expression in formalin-fixed paraffin-embedded tissue. Blood. 2014; 123(8):1214-1217.","DOI":"10.1182\/blood-2013-11-536433"},{"key":"28974","doi-asserted-by":"crossref","unstructured":"Scott DW, Mottok A, Ennishi D. Prognostic significance of diffuse large B-cell lymphoma cell of origin determined by digital gene expression in formalin-Fixed paraffin- embedded tissue biopsies. J Clin Oncol. 2015; 33(26):2848-2856.","DOI":"10.1200\/JCO.2014.60.2383"},{"key":"28975","doi-asserted-by":"crossref","unstructured":"Painter D, Barrans S, Lacy S. Cell-of-origin in diffuse large B-cell lymphomafindings from the UK\u2019s population-based Haematological Malignancy Research Network. Br J Haematol. 2019; 185(4):752-806.","DOI":"10.1111\/bjh.15619"},{"key":"28976","doi-asserted-by":"crossref","unstructured":"Veldman-Jones MH, Lai Z, Wappett M. Reproducible, quantitative, and flexible molecular subtyping of clinical DLBCL samples using the NanoString nCounter System. Clin Cancer Res. 2015; 21(10):2367-2378.","DOI":"10.1158\/1078-0432.CCR-14-0357"},{"key":"28977","doi-asserted-by":"crossref","unstructured":"Rimsza LM, Wright G, Schwartz M. Accurate classification of diffuse large B-cell lymphoma into germinal center and activated B-cell subtypes using a nuclease protection assay on formalin-fixed, paraffinembedded tissues. Clin Cancer Res. 2011; 17(11):3727-3732.","DOI":"10.1158\/1078-0432.CCR-10-2573"},{"key":"28978","doi-asserted-by":"crossref","unstructured":"Younes A, Sehn LH, Johnson P. Randomized phase III trial of ibrutinib and rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone in non-germinal center B-cell diffuse large B-cell lymphoma. J Clin Oncol. 2019; 37(15):1285-1295.","DOI":"10.1200\/JCO.18.02403"},{"key":"28979","doi-asserted-by":"crossref","unstructured":"Vitolo U, Witzig T, Gascoyne R. ROBUST: first report of phase III randomized study of lenalidomide\/R CHOP (R2 CHOP) vs placebo\/R CHOP in previously untreated ABC type diffuse large B cell lymphoma. Hematol Oncol. 2019; 37(S2):36-37.","DOI":"10.1002\/hon.5_2629"},{"key":"28980","doi-asserted-by":"crossref","unstructured":"Davies A, Cummin TE, Barrans S. Gene-expression profiling of bortezomib added to standard chemoimmunotherapy for diffuse large B-cell lymphoma (REMoDLB): an open-label, randomised, phase 3 trial. Lancet Oncol. 2019; 20(5):649-662.","DOI":"10.1016\/S1470-2045(18)30935-5"},{"key":"28981","doi-asserted-by":"crossref","unstructured":"Green TM, Young KH, Visco C. Immunohistochemical double-hit score is a strong predictor of outcome in patients with diffuse large B-cell lymphoma treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone. J Clin Oncol. 2012; 30(28):3460-3467.","DOI":"10.1200\/JCO.2011.41.4342"},{"key":"28982","doi-asserted-by":"crossref","unstructured":"Johnson NA, Slack GW, Savage KJ. Concurrent expression of MYC and BCL2 in diffuse large B-cell lymphoma treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone. J Clin Oncol. 2012; 30(28):3452-3459.","DOI":"10.1200\/JCO.2011.41.0985"},{"key":"28983","doi-asserted-by":"crossref","unstructured":"taiger AM, Ziepert M, Horn H. Clinical impact of the Cell-of-Origin Classification and the MYC\/ BCL2 dual expresser status in diffuse large B-cell lymphoma treated within prospective clinical trials of the German High-Grade Non-Hodgkin's Lymphoma Study Group. 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