Lamin B1 safeguards the B cell genome and shapes lymphoma outcome.

Lamin B1 is a structural component of the nuclear lamina that participates in genome organization and transcriptional control. 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-derived 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-strand breaks), we identified nonrandom double-strand 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-cell 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-derived malignancies.