An oscillatory lymphomagenesis circuit model. (A) On reactivation, normal MBs undergo terminal plasmacytic differentiation or, less frequently, populate new GC reactions. Key TFs involved in these processes are highlighted at the bottom of the scheme. (B) During MCD/C5 and PENLs transformation, MB-like CPCs are proposed to get caught in an oscillatory lymphomagenic state. In this scenario, CPCs with low TLR and BCR signaling thresholds become repeatedly reactivated, but unlike normal MBs, their complete differentiation into PC or GCB is blocked by somatic mutations (as exemplified at the bottom of the scheme). Hence, CPCs instead reversibly swing between early PB and pre-GCB states, undergoing bursts of proliferation and AID activation, favoring the acquisition of ulterior mutations needed to achieve immune evasion, and accounting for the aberrant MB-like presentation of these tumors. (C) WM malignant transformation may follow similar or identical initial trajectories than MC/C5s by forming MB-like CPCs. However, somatic mutations in WM are expected to block the GCB cell fate but allow plasmacytic differentiation, accounting for the distinctive LLPC-like presentation of these tumors.