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Chronic-active BCR signaling, typical for the more aggressive activated B-cell subtype (ABC) of DLBCLs, is often attributed to activating mutations within the BCR signaling cascade and continuous stimulation of the BCR by autoantigens. In certain ABC-DLBCLs, the BCR forms an intracellular multiprotein supercomplex with TLR9 and MYD88, which generates signals from endolysosomes. However, it is not clear whether the internalization of BCR is required for sustained signaling, nor have the mechanisms responsible for BCR trafficking been defined. To address these questions, we developed DLBCL cell models with modified ovalbumin (OVA)-specific hypervariable regions (HVRs) in the BCRs using CRISPR-Cas9 technology. Modified BCRs were incapable of binding self-antigens, while still responding in a controlled fashion to stimulation with ovalbumin. Using these genetic models, we demonstrated that autoantigens drive a complex BCR-dependent signaling program and facilitate the assembly of the intracellular BCR-TLR9-I\u03baB complex, promoting NF\u03baB pathway activation. Furthermore, we showed that the binding of autoantigens to the BCR leads to the internalization of the BCR\u2013autoantigen complex via clathrin-mediated endocytosis (CME). Using genetic models with inducible inhibition of this endocytic pathway, we found that BCR internalization is essential for the oncogenic activation of the BCR-dependent signaling pathways and the formation of the BCR-TLR9-I\u03baB complex in autoantigen-dependent ABC-DLBCL cells. Finally, CME inhibition with dynamin-2 antagonists, such as phenothiazine derivatives, reduces BCR signaling, cell viability, and synergizes with SYK and PI3K\u03b4 inhibitors. Since phenothiazines have well-defined safety and pharmacokinetic profiles, our data provide a framework for the rational design of clinical trials employing these drugs in the autoantigen-dependent subset of DLBCL.<\/jats:p>","DOI":"10.1038\/s41419-026-08446-1","type":"journal-article","created":{"date-parts":[[2026,2,11]],"date-time":"2026-02-11T09:35:02Z","timestamp":1770802502000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Inhibition of autoantigen-induced B-cell receptor (BCR) internalization as a therapeutic strategy in diffuse large B cell lymphoma (DLBCL)"],"prefix":"10.1038","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2920-2672","authenticated-orcid":false,"given":"Patryk","family":"G\u00f3rniak","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8686-3429","authenticated-orcid":false,"given":"Anna","family":"Polak","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anna","family":"Rams","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kristyna","family":"Kupcova","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eliza","family":"G\u0142odkowska-Mr\u00f3wka","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zofia","family":"Pilch","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marta","family":"Mi\u0105czy\u0144ska","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2748-9523","authenticated-orcid":false,"given":"Dominika","family":"Nowis","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2830-5100","authenticated-orcid":false,"given":"Jakub","family":"Go\u0142\u0105b","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"R. 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