Cyclic MB reactivation as a pathogenic mechanism. (A) GC re-entry as a lymphomagenesis mechanism. Under normal conditions, only a limited subset of MBs partake in new GC reactions after reactivation. In the early stages of malignant transformation, founder mutations, acquired by GCBs as SHM off-target byproducts or resulting from DNA replication errors, can exacerbate this mechanism by producing a set of aberrant MBs that progressively outcompete NB and wild-type (WT) MBs in seeding new GC reactions, favoring their clonal expansion. Concomitantly, participation in successive GC reactions is predicted to result in cumulative acquisition of further off-target mutations in these cells. Such a process is envisioned to take place over long periods of time, ultimately generating an MB-like CPC population. Plasmacytic differentiation, both as another possible GC output and as alternative cell-fate during MB reactivation, is omitted from the scheme for the sake of simplicity but is expected to be impaired by founder or secondary mutations. (B) Epigenetic, transcriptional, and phenotypic reprogramming induced by TBL1XR1 mutations. TFs BCL6, BACH2, and BLIMP1 are required for GCB, MB, and PC development, respectively. (i) In WT GCBs, BCL6 and BACH2 bind to the PRDM1 (BLIMP1) locus and repress its expression, blocking PC differentiation. Transient repression of gene enhancers linked to terminal differentiation by BCL6 and TBL1XR1/SMRT/HDAC3 complexes further prevents MB and PC formation. (ii) TBL1XR1 mutations, as probable founder events, reprogram SMRT/HDAC3 binding from BCL6 to BACH2, causing de-repression of genes required for GCB differentiation, and potentiating the BACH2-driven MB program. Continued repression of PRMD1 by BACH2 maintains GCBs away from the PC fate and shuttles them into an aberrant MB-like state, involved in MCD/C5s early transformation.