ARID1A mutations protect follicular lymphoma from FAS-dependent immune surveillance by reducing RUNX3/ETS1-driven FAS-expression

The cell death receptor FAS and its ligand (FASLG) play crucial roles in the selection of B cells during the germinal center (GC) reaction. Failure to eliminate potentially harmful B cells via FAS can lead to lymphoproliferation and the development of B cell malignancies. The classic form of follicular lymphoma (FL) is a prototypic GC-derived B cell malignancy, characterized by the t(14;18)(q32;q21)IGH::BCL2 translocation and overexpression of antiapoptotic BCL2. Additional alterations were shown to be clinically relevant, including mutations in ARID1A. ARID1A is part of the SWI/SNF nucleosome remodeling complex that regulates DNA accessibility ("openness"). However, the mechanism how ARID1A mutations contribute to FL pathogenesis remains unclear. We analyzed 151 FL biopsies of patients with advanced-stage disease at initial diagnosis and found that ARID1A mutations were recurrent and mainly disruptive, with an overall frequency of 18%. Additionally, we observed that ARID1A mutant FL showed significantly lower FAS protein expression in the FL tumor cell population. Functional experiments in BCL2-translocated lymphoma cells demonstrated that ARID1A is directly involved in the regulation of FAS, and ARID1A loss leads to decreased FAS protein and gene expression. However, ARID1A loss did not affect FAS promotor openness. Instead, we identified and experimentally validated a previously unknown co-transcriptional complex consisting of RUNX3 and ETS1 that regulates FAS expression, and ARID1A loss leads to reduced RUNX3 promotor openness and gene expression. The reduced FAS levels induced by ARID1A loss rendered lymphoma cells resistant to both soluble and T cell membrane-anchored FASLG-induced apoptosis, and significantly diminished CAR T cell killing in functional experiments. In summary, we have identified a functionally and clinically relevant mechanism how FL cells can escape FAS-dependent immune surveillance, which may also impact the efficacy of T cell-based therapies, including CAR T cells.

Authors

Institutions

Publication Details

Journal
Cell Death and Differentiation
Published
2025-01-22
DOI
https://doi.org/10.1038/s41418-025-01445-3
Citations
4
Primary Topic
Immune Cell Function and Interaction
Type
article
Field-Weighted Citation Impact
3.19

Funders

Controls
|||
ALL TIME
JAN
FEB
MAR
APR
MAY
JUN
JUL
AUG
SEP
OCT
article

ARID1A mutations protect follicular lymphoma from FAS-dependent immune surveillance by reducing RUNX3/ETS1-driven FAS-expression

Verena Passerini, Marion Subklewe, Lucas Esteban Wange, Martina Rudelius et al.
4 citations
Cell Death and Differentiation
Immune Cell Function and Interaction
3.19
article

ARID1A mutations protect follicular lymphoma from FAS-dependent immune surveillance by reducing RUNX3/ETS1-driven FAS-expression

Verena Passerini, Marion Subklewe, Lucas Esteban Wange, Martina Rudelius, Wolfgang Enard, Michael Heide, Michael von Bergwelt‐Baildon, Susanne Thieme, Carolin Dorothea Strobl, Johannes Adrian Hildebrand, Sebastian Bultmann, Martina Antoniolli, Maria Solovey, Heinrich Leonhardt, Julia Mergner, Oliver Weigert, Lis Winter, Maria Colomé‐Tatché, William Keay, Helmut Blum, Louisa Adolph, Deepak Bararia, Marc Schmidt‐Supprian, Christina Ludwig, Tabea Freyholdt
article en
4 citations

Abstract

The cell death receptor FAS and its ligand (FASLG) play crucial roles in the selection of B cells during the germinal center (GC) reaction. Failure to eliminate potentially harmful B cells via FAS can lead to lymphoproliferation and the development of B cell malignancies. The classic form of follicular lymphoma (FL) is a prototypic GC-derived B cell malignancy, characterized by the t(14;18)(q32;q21)IGH::BCL2 translocation and overexpression of antiapoptotic BCL2. Additional alterations were shown to be clinically relevant, including mutations in ARID1A. ARID1A is part of the SWI/SNF nucleosome remodeling complex that regulates DNA accessibility ("openness"). However, the mechanism how ARID1A mutations contribute to FL pathogenesis remains unclear. We analyzed 151 FL biopsies of patients with advanced-stage disease at initial diagnosis and found that ARID1A mutations were recurrent and mainly disruptive, with an overall frequency of 18%. Additionally, we observed that ARID1A mutant FL showed significantly lower FAS protein expression in the FL tumor cell population. Functional experiments in BCL2-translocated lymphoma cells demonstrated that ARID1A is directly involved in the regulation of FAS, and ARID1A loss leads to decreased FAS protein and gene expression. However, ARID1A loss did not affect FAS promotor openness. Instead, we identified and experimentally validated a previously unknown co-transcriptional complex consisting of RUNX3 and ETS1 that regulates FAS expression, and ARID1A loss leads to reduced RUNX3 promotor openness and gene expression. The reduced FAS levels induced by ARID1A loss rendered lymphoma cells resistant to both soluble and T cell membrane-anchored FASLG-induced apoptosis, and significantly diminished CAR T cell killing in functional experiments. In summary, we have identified a functionally and clinically relevant mechanism how FL cells can escape FAS-dependent immune surveillance, which may also impact the efficacy of T cell-based therapies, including CAR T cells.

Cell Death and DifferentiationVol. 32(5)
Medigene (Germany) (DE), German Cancer Research Center (DE), Heidelberg University (DE), TUM Klinikum (DE), Helmholtz Zentrum München (DE), LMU Klinikum (DE), Munich Leukemia Laboratory (Germany) (DE), Urologische Klinik München (DE), Deutsches Konsortium für Translationale Krebsforschung (DE), Technical University of Munich (DE), Ludwig-Maximilians-Universität München (DE), Epigenomics (Germany) (DE)
Lymphoma Research Foundation, Wilhelm Sander-Stiftung, Deutsche Forschungsgemeinschaft, Else Kröner-Fresenius-Stiftung, Ludwig-Maximilians-Universität München
Good health and well-being
Openalex Percentile: Top 9%
Immune Cell Function and Interaction
3.19
DOIOpen Access PDFOpenAlex
AI Navigator

Ask Laika to Summarize, Analyze, and Connect papers live on the map.

Summarize Papers & Methodologies

Extract key findings, datasets, and comparative methods across publications.

Benchmark Rankings & Visual Analytics

Rank top research institutions, authors, funders, topics, and journals by Field-Weighted Citation Impact (FWCI) and paper volume with instant charts.

Connect Distant Disciplines

Bridge topological clusters on the map to find hidden collaborative intersections.