The B‐cell receptor in control of tumor B‐cell fitness: Biology and clinical relevance

Summary Surface expression of a functional B cell antigen receptor ( BCR ) is essential for the survival and proliferation of mature B cells. Most types of B‐cell lymphoproliferative disorders retain surface BCR expression, including B‐cell non‐Hodgkin lymphomas (B‐ NHL ) and chronic lymphocytic leukemia ( CLL ). Targeting BCR effectors in B‐ NHL cell lines in vitro has indicated that this signaling axis is crucial for malignant B cell growth. This has led to the development of inhibitors of BCR signaling, which are currently used for the treatment of CLL and several B‐ NHL subtypes. Recent studies based on conditional BCR inactivation in a MYC ‐driven mouse B‐cell lymphoma model have revisited the role of the BCR in MYC ‐expressing tumor B cells. Indeed, lymphoma cells losing BCR expression continue to grow unless subjected to competition with their BCR ‐expressing counterparts, which causes their elimination. Here, we discuss the molecular nature of the fitness signal delivered by the BCR to MYC ‐expressing malignant B cells, ensuring their preferential persistence within a rapidly expanding tumor population. We also review growing evidence of Ig‐negative cases belonging to several B‐ NHL subtypes and CLL , and discuss the clinical implications of these findings in relation to an emerging picture of clinical resistances to anti‐ BCR therapies.