PXD041408-1

PXD041408 is an original dataset announced via ProteomeXchange.

Title	ARID1A mutations protect follicular lymphoma from FAS-dependent immune surveillance by reducing RUNX3/ETS1-driven FAS-expression
Description	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.
HostingRepository	PanoramaPublic
AnnounceDate	2025-10-01
AnnouncementXML	Submission_2025-10-01_09:41:52.929.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Supported dataset by repository
PrimarySubmitter	Julia Mergner
SpeciesList	scientific name: Homo sapiens; NCBI TaxID: 9606;
ModificationList	Carbamidomethyl
Instrument	Q Exactive HF-X

Revision	Datetime	Status	ChangeLog Entry
0	2023-04-07 16:26:52	ID requested
⏵ 1	2025-10-01 09:41:53	announced

Antoniolli M, Solovey M, Hildebrand JA, Freyholdt T, Strobl CD, Bararia D, Keay WD, Adolph L, Heide M, Passerini V, Winter L, Wange L, Enard W, Thieme S, Blum H, Rudelius M, Mergner J, Ludwig C, Bultmann S, Schmidt-Supprian M, Leonhardt H, Subklewe M, von Bergwelt-Baildon M, Colom, é, -Tatch, é M, Weigert O, ARID1A mutations protect follicular lymphoma from FAS-dependent immune surveillance by reducing RUNX3/ETS1-driven FAS-expression. Cell Death Differ, 32(5):899-910(2025) [pubmed]

submitter keyword: FAS, cell surface, parallel reaction monitoring

Christina Ludwig
contact affiliation	BayBioMS, Technical University of Munich
contact email	tina.ludwig@tum.de
lab head
Julia Mergner
contact affiliation	BayBioMS@MRI, Technical University of Munich
contact email	julia.mergner@tum.de
dataset submitter

Panorama Public dataset URI