The B-cell Receptor Blueprint in Lymphoma: Mechanisms and Therapeutic Opportunities

The B-cell receptor (BCR) is central to normal and malignant B-cell biology, integrating intrinsic programs with microenvironmental cues to shape cell fate. Across mature B-cell lymphomas, differences in BCR expression, class, and signaling mode define distinct pathogenetic routes and therapeutic vulnerabilities, ranging from BCR-dependent to BCR-silent states. We propose a BCR blueprint that positions these tumors along a continuum of signaling modes and class-imposed functions, emphasizing germinal center-derived lymphomas. This framework links specific BCR states to genetic lesions and microenvironmental niches, underscoring the value of routinely monitoring BCR features to track tumor evolution and inform therapy. Significance: B-cell lymphomas exploit diverse BCR expression levels, classes, and signaling modes that span BCR-addicted to BCR-silent states and shape their genetic programs and therapeutic dependencies. A unified BCR blueprint reframes these diseases along a continuum of BCR signaling and isotype-driven biology, particularly in germinal center-derived entities. Embedding this blueprint into routine clinical testing has the potential to improve prediction of response or resistance to BCR-targeted and other mechanism-based therapies.