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During adaptive immune responses, B lymphocytes in germinal centers (GCs) undergo clonal expansion and programmed DNA damage at immunoglobulin loci, while simultaneously downregulating Lamin B1. Likewise, Lamin B1 downregulation has been observed in GC\u2010derived lymphomas and myeloid malignancies, yet the functional consequences of Lamin B1 loss during B cell development remain poorly understood. Here, we used in vivo and in vitro B cell models of conditional hypomorphic Lamin B1 expression, which showed elevated DNA damage and disrupted transcriptional profiles. Using sBLISS (in situ labeling and sequencing of double\u2010strand breaks), we identified nonrandom double\u2010strand break hotspots in both mouse and human GC B cells depleted of Lamin B1. These breaks are preferentially located near transcriptional start sites (TSSs) and regulatory elements that control translation and mRNA fate, suggesting Lamin B1 has a role in protecting regulatory genomic regions. Moreover, low LMNB1 expression is associated with poor clinical outcomes in patients with diffuse large B\u2010cell lymphoma (DLBCL). Together, this study reveals a crucial role for Lamin B1 in preserving genomic stability in B cells, underscoring its impact on the pathogenesis of B cell\u2010derived malignancies.<\/jats:p>","DOI":"10.1002\/hem3.70387","type":"journal-article","created":{"date-parts":[[2026,6,7]],"date-time":"2026-06-07T09:30:09Z","timestamp":1780824609000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Lamin B1 safeguards the B cell genome and shapes lymphoma outcome"],"prefix":"10.1002","volume":"10","author":[{"given":"Filip","family":"Filipsky","sequence":"first","affiliation":[{"name":"Centre for Haemato\u2010Oncology, Barts Cancer Institute, Queen Mary University of London, 3rd Floor John Vane Science Centre, Charterhouse Square London UK"},{"name":"Department of Biomedicine University Hospital and University of Basel Basel Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katarina 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