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Genetic and Phenotypic Attributes of Splenic Marginal Zone Lymphoma

Ferdinando Bonfiglio, Alessio Bruscaggin, Francesca Guidetti, Lodovico Terzi Di Bergamo, Martin Richard Faderl, Valeria Spina, Adalgisa Condoluci, Luisella Bonomini, Gabriela Forestieri, Ricardo Koch, Deborah Piffaretti, Katia Pini, Maria C Pirosa, Micol Giulia Cittone, Alberto Arribas, Marco Lucioni, Guido Ghilardi, Wei Wu, Luca Arcaini, Maria Joao Baptista, Gabriela Bastidas, Silvia Beà, Renzo Boldorini, Alessandro Broccoli, Marco Matteo Bühler, Vincenzo Canzonieri, Luciano Cascione, Luca Ceriani, Sergio B. Cogliatti, Paolo Corradini, Enrico Derenzini, Liliana Devizzi, Sascha Dietrich, Angela Rita Elia, Fabio Facchetti, Gianluca Gaidano, Juan F Garcia, Bernhard Gerber, Paolo Ghia, Maria Gomes Da Silva, Giuseppe Gritti, Anna Guidetti, Felicitas Hitz, Giorgio Ga Inghirami, Marco Ladetto, Armando López-Guillermo, Elisa Lucchini, Antonino Maiorana, Roberto Marasca, Estella Matutes, Véronique Meignin, Michele Merli, Alden A Moccia, Manuela Mollejo, Carlos Montalban, Urban Novak, David Graham Oscier, Francesco Passamonti, Francesco A Piazza, Stefano Pizzolitto, Alessandro Rambaldi, Elena Sabattini, Gilles Andre Salles, Elisa Santambrogio, Lydia Scarfo, Anastasios Stathis, Georg Stüssi, Julia Turbiner Geyer, Gustavo Tapia, Corrado Tarella, Catherine Thieblemont, Thomas Tousseyn, Alessandra Tucci, Giorgio Vanini, Carlo Visco, Umberto Vitolo, Renata Walewska, Francesco Zaja, Thorsten Zenz, Pier Luigi Zinzani, Hossein Khiabanian, Arianna Calcinotto, Francesco Bertoni, Govind Bhagat, Elias Campo, Laurence De Leval, Stefan Dirnhofer, Stefano A Pileri, Miguel A Piris, Alexandra Traverse-Glehen, Alexander Tzankov, Marco Paulli, Maurilio Ponzoni, Luca Mazzucchelli, Franco Cavalli, Emanuele Zucca & Davide Rossi

abstract Splenic marginal zone B-cell lymphoma (SMZL) is a heterogeneous clinico-biological entity. The clinical course is variable, multiple genes are mutated with no unifying mechanism, essential regulatory pathways and surrounding microenvironments are diverse. We sought to clarify the heterogeneity of SMZL by resolving different subgroups and their underlying genomic abnormalities, pathway signatures and microenvironment compositions to uncover biomarkers and therapeutic vulnerabilities. We studied 303 SMZL spleen samples collected through the IELSG46 multicenter, international study (NCT02945319) by using a multiplatform approach. We carried out genetic and phenotypic analyses, defined self-organized signatures, validated the findings in independent primary tumor meta-data and in genetically modified mouse models, and determined correlations with outcome data. We identified two prominent genetic clusters in SMZL, termed NNK (58% of cases, harboring NF-κB, NOTCH and KLF2 modules) and DMT (32% of cases, with DNA-damage response, MAPK and TLR modules). Genetic aberrations in multiple genes as well as cytogenetic and immunogenetic features distinguished NNK- from DMT-SMZLs. These genetic clusters not only have distinct underpinning biology, as judged by differences in gene-expression signatures, but also different outcome, with inferior survival in NNK-SMZLs. Digital cytometry and in situ profiling segregated two basic types of SMZL immune microenvironments termed immune-suppressive SMZL (50% of cases, associated with inflammatory cells and immune checkpoint activation) and immune-silent SMZL (50% of cases, associated with an immune-excluded phenotype) with distinct mutational and clinical connotations. In summary, we propose a nosology of SMZL that can implement its classification and also aid in the development of rationally targeted treatments.
   
citation Bonfiglio F, Bruscaggin A, Guidetti F, Terzi Di Bergamo L, Faderl M R, Spina V, Condoluci A, Bonomini L, Forestieri G, Koch R, Piffaretti D, Pini K, Pirosa M C, Cittone M G, Arribas A, Lucioni M, Ghilardi G, Wu W, Arcaini L, Baptista M J, Bastidas G, Beà S, Boldorini R, Broccoli A, Bühler M M, Canzonieri V, Cascione L, Ceriani L, Cogliatti S B, Corradini P, Derenzini E, Devizzi L, Dietrich S, Elia A R, Facchetti F, Gaidano G, Garcia J F, Gerber B, Ghia P, Gomes Da Silva M, Gritti G, Guidetti A, Hitz F, Inghirami G G, Ladetto M, López-Guillermo A, Lucchini E, Maiorana A, Marasca R, Matutes E, Meignin V, Merli M, Moccia A A, Mollejo M, Montalban C, Novak U, Oscier D G, Passamonti F, Piazza F A, Pizzolitto S, Rambaldi A, Sabattini E, Salles G A, Santambrogio E, Scarfo L, Stathis A, Stüssi G, Geyer J T, Tapia G, Tarella C, Thieblemont C, Tousseyn T, Tucci A, Vanini G, Visco C, Vitolo U, Walewska R, Zaja F, Zenz T, Zinzani P L, Khiabanian H, Calcinotto A, Bertoni F, Bhagat G, Campo E, De Leval L, Dirnhofer S, Pileri S A, Piris M A, Traverse-Glehen A, Tzankov A, Paulli M, Ponzoni M, Mazzucchelli L, Cavalli F, Zucca E, Rossi D. Genetic and Phenotypic Attributes of Splenic Marginal Zone Lymphoma. Blood 2021;.
   
type journal paper/review (English)
date of publishing 15-10-2021
journal title Blood
ISSN electronic 1528-0020
PubMed 34653238
DOI 10.1182/blood.2021012386