Lamin B1 Safeguards the B Cell Genome and Shapes Lymphoma Outcome

Abstract

Lamin B1 is a structural component of the nuclear lamina that participates in diverse cellular processes, including genome regulation and cellular senescence. During adaptive immune responses, B lymphocytes in germinal centres (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 expression of Lamin B1, which showed elevated DNA damage, altered chromatin accessibility, and disrupted transcriptional profiles. Using sBLISS (in situ labelling and sequencing of double-strand breaks), we identified non-random 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, implicating Lamin B1 in protecting fragile regulatory regions. Moreover, low LMNB1 expression correlated 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.