Antigenic drivers and immune context of MB reactivation. (A) Aberrant redemption of self-reactive B cells as an early lymphomagenic event. Anergic B cells whose BCRs recognize both self- and foreign antigens can be recruited into GC reactions if activated by the latter. (i) Once inside the GC, these B cells can redeem themselves and terminally differentiate if BCR SHM causes them to increase their affinity for the foreign antigen while minimizing their reaction against self. (ii) If the edited BCR does not portray a corrected affinity balance or if it acquires a stronger self-reactive character, GCBs are selected to undergo cell death. (iii) However, concomitant somatic mutations outside the BCR locus, such as those targeting BCL2 and TBL1XR1, hold the potential to aberrantly spare self-reactive cells, allowing them to egress the GC, and persist as MBs capable or reactivating, in a fashion reminiscent of aged/autoimmune B cells ("ABCs," discussed in main text). Persistent reactivation of these cells by self-antigens could then sustain the malignant transformation process. (B) Alternative niches and compartments for B-cell malignant transformation. Although founder mutations in primary and secondary extranodal lymphoma (SENLs) most likely occur in the context of canonical GC reactions, further transformation might follow alternative trajectories. Mixed and strictly non–GC-dependent transformation models might better account for the pathogenesis of PENLs, particularly those targeting immune-privileged organs (discussed in main text).