期刊
BLOOD
卷 139, 期 5, 页码 732-747出版社
AMER SOC HEMATOLOGY
DOI: 10.1182/blood.2021012386
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资金
- Swiss Cancer Research, Bern, Switzerland [3746, 4395, 4660, 4705]
- Research Advisory Board of the Ente Ospedaliero Cantonale, Bellinzona, Switzerland [ABREOC 2019-22514]
- European Research Council (ERC) Consolidator Grant CLLCLONE [772051]
- Swiss National Science Foundation, Berne, Switzerland [320030_169670/1, 310030_192439, 320036_179318]
- Fondazione Ticinese Contro il Cancro, Fondazione Fidinam, Lugano, Switzerland
- Nelia & Amadeo Barletta Foundation, Lausanne, Switzerland
- Fond'Action, Lausanne, Switzerland
- Leukemia & Lymphoma Society, Translational Research Program, New York, NY [6594-20]
- AFRI, Ente Ospedaliero Cantonale, Bellinzona, Switzerland
- Fondazione Ettore Balli, Associazione Italiana Ricerca sul Cancro, Special 5x1000 Program Metastases [21198]
- Swiss National Science Foundation (SNF) [310030_192439] Funding Source: Swiss National Science Foundation (SNF)
- European Research Council (ERC) [772051] Funding Source: European Research Council (ERC)
Splenic marginal zone B-cell lymphoma (SMZL) is a heterogeneous clinico-biological entity with different subgroups characterized by genetic abnormalities, pathway signatures, and microenvironment compositions. These findings provide insights into the classification and treatment of SMZL.
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, and 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 multiplat-form approach. We carried out genetic and phenotypic analyses, defined self-organized signatures, validated the findings in independent primary tumor metadata and determined correlations with outcome data. We identified 2 prominent genetic clusters in SMZL, termed NNK (58% of cases, harboring NF-kappa B, NOTCH, and KLF2 modules) and DMT (32% of cases, with DNA-damage response, MAPIC, 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 outcomes, with inferior survival in NNK-SMZLs. Digital cytometry and in situ profiling segregated 2 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.
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