Genetic and phenotypic attributes of splenic marginal zone lymphoma

• DOI: 10.1182/blood.2021012386
• Publication Date: 2021-10-20T17:54:43Z
• Authors: Ferdinando Bonfiglio; Alessio Bruscaggin; Francesca Guidetti; Lodovico Terzi di...; Martin Faderl; Valeria Spina; Adalgisa Condoluci; Luisella Bonomini; Gabriela Forestieri; Ricardo Koch; Deborah Piffaretti; Katia Pini; Maria Cristina Pi...; Micol Giulia Cittone; Alberto Arribas; Marco Lucioni; Guido Ghilardi; Wei Wu; Luca Arcaini; Maria Joao Baptista; Gabriela Bastidas; Silvia Bea; Renzo Boldorini; Alessandro Broccoli; Marco Matteo Buehler; Vincenzo Canzonieri; Luciano Cascione; Luca Ceriani; Sergio Cogliatti; Paolo Corradini; Enrico Derenzini; Liliana Devizzi; Sascha Dietrich; Angela Rita Elia; Fabio Facchetti; Gianluca Gaidano; Juan Fernando Garcia; Bernhard Gerber; Paolo Ghia; Maria Gomes da Silva; Giuseppe Gritti; Anna Guidetti; Felicitas Hitz; Giorgio Inghirami; Marco Ladetto; Armando Lopez-Gui...; Elisa Lucchini; Antonino Maiorana; Roberto Marasca; Estella Matutes; Veronique Meignin; Michele Merli; Alden Moccia; Manuela Mollejo; Carlos Montalban; Urban Novak; David Graham Oscier; Francesco Passamonti; Francesco Piazza; Stefano Pizzolitto; Alessandro Rambaldi; Elena Sabattini; Gilles Salles; Elisa Santambrogio; Lydia Scarfò; Anastasios Stathis; Georg Stüssi; Julia T. Geyer; Gustavo Tapia; Corrado Tarella; Catherine Thieble...; 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 Travers...; Alexander Tzankov; Marco Paulli; Maurilio Ponzoni; Luca Mazzucchelli; Franco Cavalli; Emanuele Zucca; Davide Rossi
• Keywords: Male; 0301 basic medicine; Lymphoma; [SDV]Life Sciences [q-bio]; Marginal Zone; Mice; NOTCH2; Tumor Microenvironment; genetics; Splenic marginal zone lymphoma; 0303 health sciences; 600; Hematology; Middle Aged; SUBSET; Splenic Neoplasm; PREVALENCE; 3. Good health; GENOME; Genetic, phenotypic, splenic marginal zone lymphoma; Multigene Family; INACTIVATION; Female; Life Sciences & Biomedicine; Human; EXPRESSION; phenotype; Aged; Animals; Chromosome Aberrations; Female; Humans; Immunophenotyping; Lymphoma, B-Cell, Marginal Zone; Male; Mice; Middle Aged; Multigene Family; Mutation; Spleen; Splenic Neoplasms; Transcriptome; Tumor Microenvironment; 610; 610 Medicine & health; DIAGNOSIS; Chromosome Aberration; Immunophenotyping; 03 medical and health sciences; Aged; Animals; Chromosome Aberrations; Female; Humans; Immunophenotyping; Lymphoma, B-Cell, Marginal Zone/diagnosis; Lymphoma, B-Cell, Marginal Zone/genetics; Male; Mice; Middle Aged; Multigene Family; Mutation; Spleen/pathology; Splenic Neoplasms/diagnosis; Splenic Neoplasms/genetics; Transcriptome; Tumor Microenvironment; Animals; Humans; SMZL. molecular oncology; Aged; Chromosome Aberrations; Science & Technology; Animal; MUTATIONS; Splenic Neoplasms; B-Cell; Lymphoma, B-Cell, Marginal Zone; mutations; DELETIONS; B-CELL LYMPHOMAS; Mutation; Transcriptome; Spleen

Splenic marginal zone B-cell lymphoma (SMZL) is a heterogeneous clinico-biological entity. The clinical course variable, multiple genes are mutated with no unifying mechanism, and essential regulatory pathways surrounding microenvironments diverse. We sought to clarify the heterogeneity of SMZL by resolving different subgroups their underlying genomic abnormalities, pathway signatures, microenvironment compositions uncover biomarkers therapeutic vulnerabilities. studied 303 spleen samples collected through IELSG46 multicenter international study (NCT02945319) using multiplatform approach. carried out genetic phenotypic analyses, defined self-organized validated findings in independent primary tumor metadata genetically modified mouse models, determined correlations outcome data. identified 2 prominent clusters SMZL, termed NNK (58% cases, harboring NF-κB, NOTCH, KLF2 modules) DMT (32% DNA-damage response, MAPK, TLR modules). Genetic aberrations as well cytogenetic immunogenetic features distinguished NNK- from DMT-SMZLs. These not only have distinct underpinning biology, judged differences gene-expression but also outcomes, inferior survival NNK-SMZLs. Digital cytometry situ profiling segregated basic types immune immune-suppressive (50% associated inflammatory cells checkpoint activation) immune-silent an immune-excluded phenotype) mutational connotations. In summary, we propose nosology that can implement its classification aid development rationally targeted treatments.