TY - JOUR AU - Enrico Derenzini, AU - Saveria Mazzara, AU - Federica Melle, AU - Giovanna Motta, AU - Marco Fabbri, AU - Riccardo Bruna, AU - Claudio Agostinelli, AU - Alessandra Cesano, AU - Chiara Antonia Corsini, AU - Ning Chen, AU - Simona Righi, AU - Elena Sabattini, AU - Annalisa Chiappella, AU - Angelica Calleri, AU - Stefano Fiori, AU - Valentina Tabanelli, AU - Antonello Cabras, AU - Giancarlo Pruneri, AU - Umberto Vitolo, AU - Alessandro Massimo Gianni, AU - Alessandro Rambaldi, AU - Paolo Corradini, AU - Pier Luigi Zinzani, AU - Corrado Tarella, AU - Stefano Pileri, PY - 2021/09/01 Y2 - 2024/03/29 TI - A three-gene signature based on <i>MYC</i>, <i>BCL-2</i> and <i>NFKBIA</i> improves risk stratification in diffuse large B-cell lymphoma JF - Haematologica JA - haematol VL - 106 IS - 9 SE - Articles DO - 10.3324/haematol.2019.236455 UR - https://haematologica.org/article/view/9913 SP - 2405-2416 AB - 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. ER -