Stepwise model for MCD/C5s and PENLs pathogenesis. (1) During normal immune responses, SHM or DNA replication errors stochastically introduce off-target founder mutations in GCBs, favoring the development of an immature long-lived MB population with increased tendency to acquire a GCB-like profile on recall, at the expense of terminal PC differentiation. (2) Cyclic reactivation of these MBs over extended periods of time favors their clonal expansion and increases the chances of acquiring additional off-target mutations. Repeated activation may be driven by a self-reactive BCR or chronic exposure to foreign agents and could occur in the context of canonical GCs or in a GC-independent manner. (3) Founder or secondary-acquired mutations, targeting BCR and TLR pathway mediators, lower the immune activation threshold of these MB-like CPCs, driving them into a semipersistent activated state. At this stage, cells are predicted to become less dependent on canonical costimulatory signaling. (4) Persistent activation in the context of MBs intrinsic phenotypic plasticity traps CPCs in a nearly cell-autonomous oscillatory state, navigating between MB-like, pre-GC–like, and PB-like phases, whereas somatic mutations block full lineage commitment. (5) These CPCs intermittently undergo bursts of proliferation and AID activation, allowing the acquisition of ulterior genomic lesions that, paired with transcriptional/epigenetic remodeling, enable complete immune evasion and overt tumor development.